Methods, compounds, and compositions for delivering 1,3-propanedisulfonic acid

ABSTRACT

The invention relates to methods, compounds, and compositions for delivering 1,3-propanedisulfonic acid (1,3PDS) in a subject, preferably a human subject. The invention encompasses compounds that will yield or generate 1,3PDS, either in vitro or in vivo. The invention also relates to sulfonate ester prodrugs of 1,3PDS as well as Gemini dimmers and oligomers of 1,3PDS for the prevention or treatment of associated diseases and conditions.

FIELD OF THE INVENTION

The invention relates to methods, compounds and compositions fordelivering 1,3-propanedisulfonic acid (1,3PDS) in a subject, preferablya human subject. The invention encompasses compounds that will yield orgenerate 1,3PDS, either in vitro or in vivo. Preferred compounds includesulfonate ester prodrugs of 1,3PDS for use, including but not limitedto, the prevention and treatment of metabolic, renal and pancreaticdiseases and disorders, including AA amyloidosis, diabetic nephropathy,diabetes and metabolic syndrome.

BACKGROUND OF THE INVENTION

1,3-Propanedisulfonic acid (1,3PDS, eprodisate, Kiacta™) is aninvestigational new drug for the treatment of AA amyloidosis (orsecondary (AA) amyloidosis), which is a manifestation of a number ofdiseases that provoke a sustained acute phase response. Such diseasesinclude chronic inflammatory disorders, chronic local or systemicmicrobial infections, and malignant neoplasms. The most common form ofAA amyloidosis is seen as the result of long-standing inflammatoryconditions. For example, patients with Rheumatoid Arthritis or FamilialMediterranean Fever (a genetic disease) can develop AA amyloidosis.

1,3PDS has also exhibited potential activity for the treatment of renaldisorders such as diabetic nephropathy and reduction of triglycerideserum levels, such as for the treatment of dyslipidemia and vascular orcardiovascular diseases (patent application published on Oct. 11, 2007as US 2007/0238788 and PCT application published as WO 2007/125385,incorporated herein by reference in their entirety). It has also beenfound to exhibit beneficial properties in vivo against features ofmetabolic syndrome and diabetes, such as insulin and glucose levels aswell as for preserving pancreatic islets of Langherans (patentapplication published on Oct. 23, 2008 as US 2008/0262088 and PCTapplication published as WO 2008/078176, incorporated herein byreference in their entirety).

Generally, when used as a therapeutic, expected dosage of 1,3PDS to beused may range from about 800 mg to about 3200 mg per day, separated inmultiple doses throughout the day.

SUMMARY OF THE INVENTION

The invention includes methods, compounds and compositions fordelivering in a subject, preferably a human subject,1,3-propanedisulfonic acid, or salts thereof. 1,3-Propanedisulfonic acid(referred to herein as 1,3PDS) has the following structure:

According to one aspect, the present invention relates to compounds orcompositions that will yield or generate 1,3PDS after being administeredto a subject. In one embodiment, the compound that will yield 1,3PDS isa sulfonate ester prodrug of 1,3PDS. In another embodiment, the compoundthat will yield 1,3PDS is a neopentyl sulfonate ester or aneopentyl-derived sulfonate ester of 1,3PDS. In another embodiment, thecompound that will yield 1,3PDS is a mono-sulfonate ester prodrug of1,3PDS. In another embodiment, the compound is a disulfonate esterprodrug of 1,3PDS. In another embodiment, the compound that will yieldor generate 1,3PDS is an oligomer or gemini dimer of 1,3PDS whichcomprises at least one sulfonate ester of 1,3PDS. In another embodiment,the compound that will yield or generate 1,3PDS is an oligomer or geminidimer of 1,3PDS which comprises a neopentyl or neopentyl-derivedsulfonate ester of 1,3PDS. In certain embodiments, the sulfonate esterprodrugs of 1,3PDS that are capable of yielding or generating, either invitro or in vivo 1,3PDS have one of the general or specific formulae orstructures disclosed herein.

More particularly, the invention relates to compounds of any one ofFormulae I, II, II-A, III and III-A, IV and V, as well as anyembodiments and examples described in section II of the description,such as Formulae (B) to (F) and embodiments thereof, as well as theirpharmaceutically acceptable salts and solvates. The invention alsoencompasses the compounds exemplified herein, for example, CompoundsA1-A73, Compounds B1-B87, Compounds C1-C3, Compounds D1-D8, CompoundsG1-G4, Compounds N1-N18, and Compound P1, as well as theirpharmaceutically acceptable salt and solvates where applicable.

The invention also further relates to a method or process for preparingthe compounds of the invention. The invention, for example, relates to amethod for the preparation of a compound of Formula II-A as hereindescribed, comprising the steps of: a) preparing a disulfonyl chlorideof the formula: ClO₂S—(CH₂)₃—SO₂Cl; b) reacting the disulfonyl chlorideof step (a) with a compound of the formula PGOH, wherein PG is aprotecting group to produce a monosulfonyl chloride of the formula:PGO₃S—(CH₂)₃—SO₂Cl; c) reacting the monosulfonyl chloride of step (b)with an alcohol of the formula R⁴OH, wherein R⁴ is as herein describedto produce a monoprotected compound of the formula: PGO₃S—(CH₂)₃—SO₃OR⁴;and d) cleaving the protecting group from the monoprotected compound ofstep c) to produce a compound of Formula II-A. In one embodiment, step(a) comprises reacting a the disodium salt of 1,3PDS with phosphoruspentachloride. In one embodiment, the PGOH compound of step (b) isphenol and step (d) comprises reacting the monoprotected compound with asource of palladium and a source of hydrogen gas, for example palladiumhydroxide (Pd(OH)₂), an acid and hydrogen gas, for example palladiumhydroxide, acetic acid and hydrogen gas. In another embodiment, steps(b) and (c) further comprise addition of a base, for example an organicbase, for example pyridine.

The present invention also relates to pharmaceutical compositionscomprising a compound of the present invention, optionally together witha pharmaceutically acceptable carrier.

The invention also relates to the use of the compounds of the inventionfor the treatment of pancreatic and/or renal and/or metabolic and/orvascular diseases and disorders. The invention further relates to theuse of the compounds of the invention in the treatment of amyloid Aamyloidosis (AA amyloidosis). The invention further relates to the useof the compounds of the invention in the treatment or prevention ofrenal impairement in patients with AA amyloidosis. The invention alsorelates to the use of the compounds of the invention in the treatment ofrenal disorders, such as diabetic nephropathy. The invention furtherrelates to the use of the compounds of the invention in delaying theonset or the need for dialysis in renally impaired patients, e.g. inpatients with AA amyloidosis or diabetic nephropathy. The inventionfurther relates to the use of the compounds of the invention in thetreatment of dyslipidemia, hyperlipidemia, and for reducing serumtriglyceride levels. The invention further relates to the use of thecompounds of the invention in the treatment of metabolic syndrome and/ordiabetes.

In another aspect, the invention relates to the use of the compounds ofthe invention for increasing insulin levels circulating in blood inresponse to food, decreasing resistance to insulin and/or increasinginsulin sensitivity in selected tissues (e.g. fat, muscle and liver),increasing insulin secretion by pancreatic cells, increasing beta-cellsand/or islets of Langerhans neogenesis and/or regeneration of islets ofLangerhans or preventing their destruction by apoptosis, preventingapoptosis in beta-cells, and stabilizing, restoring, and/or improvingpancreatic function, and more particularly stabilizing, restoring,and/or improving beta-cells size, growth and/or function.

In another aspect, this invention relates to a method for the preventionor treatment of hyperglycemia, a disease directly related to anundesirably high glycemia or undesirably low circulating levels ofinsulin and/or low insulin secretion by pancreatic cells and/orrestoring its target organ sensitivity to its action on glucosedisposal, to a method of reducing serum glucose levels, preferably thedisease is diabetes, e.g. type 1 and/or type 2. The invention furtherincludes a method for stabilizing renal function or delaying progressionof a renal disorder.

The invention also provides methods for the treatment or prevention ofthe aforementioned diseases comprising administration of atherapeutically effective amount of a compound of the invention or acomposition comprising the same, to a subject, preferably a humansubject in need thereof.

The present invention further relates to a method for increasing thetherapeutic effectiveness of 1,3PDS comprising administering to asubject, preferably a human subject, an effective amount of a prodrug ofthe present invention.

The present invention also provides processes for converting compoundsof the invention to 1,3PDS. The conversion and/or generation of 1,3PDSinvolve contacting any of the compounds of the invention with, forexample, blood, plasma, organs and/or cells. The conversion can occur invitro or in vivo. The conversion may also occur in the presence ofenzymes capable of cleaving the prodrug bonds, including sulfonate esterbonds and amide bonds, such as peptidases, or other enzymes appropriatefor other structures herein, including those found in the blood, plasmaand/or organs.

In certain embodiments, a pharmaceutical composition, formulation, ordosage form of the present invention is capable of maintaining atherapeutically effective concentration of 1,3PDS in the plasma or bloodof a patient for a time period of at least about 1 hour, for at least 2hours, for at least 3 hours, 4 hours, for at least about 8 hours, for aperiod of at least about 12 hours, at least about 16 hours, at leastabout 20 hours, and in certain embodiments for at least about 24 hoursafter the pharmaceutical composition, formulation, or dosage formcomprising a corresponding compound according to the invention and apharmaceutically acceptable vehicle is orally administered to thepatient. In certain embodiments, a pharmaceutical composition,formulation, or dosage form of the present invention is capable ofimproving the T_(max) of 1,3PDS by at least 2 fold, or by at least 3, 4,5, 6, 7, 8, 9 or 10 fold or more. In certain embodiments, apharmaceutical composition, formulation, or dosage form of the presentinvention is capable of improving the bioavailability (% F) of 1,3PDS byat least 1.2 fold, or by at least 1.5, 1.8, 2, 2.5, 3, 4, 5, 6 fold ormore. In certain embodiments, a pharmaceutical composition, formulation,or dosage form of the present invention is capable of improving the AUCof 1,3PDS by at least 1.2 fold, or by at least 1.5, 1.8, 2, 2.5, 3, 4,5, 6 fold or more.

Additional objects, advantages and features of the present inventionwill become more apparent upon reading of the following non-restrictivedescription of preferred embodiments which are exemplary and should notbe interpreted as limiting the scope of the invention.

DETAILED DESCRIPTION I. Definitions

All technical and scientific terms used herein have the same meaning ascommonly understood by one ordinary skilled in the art to which theinvention pertains. For convenience, the meaning of certain terms andphrases used herein are provided below.

To the extent the definitions of terms in the publications, patents, andpatent applications incorporated herein by reference are contrary to thedefinitions set forth in this specification, the definitions in thisspecification control. The section headings used herein are fororganizational purposes only, and are not to be construed as limitingthe subject matter disclosed.

It should be noted that, the singular forms “a”, “an”, and “the” includeplural referents unless the content clearly dictates otherwise. Thus,for example, reference to a composition containing “a compound” includesa mixture of two or more compounds. It should also be noted that theterm “or” is generally employed in its sense including “and/or” unlessthe content clearly dictates otherwise.

Abbreviations may also be used throughout the application, unlessotherwise noted, such abbreviations are intended to have the meaninggenerally understood by the field. Examples of such abbreviationsinclude Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu(butyl), t-Bu (tert-butyl), i-Bu (iso-butyl), s-Bu (sec-butyl), c-Bu(cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z(carbobenzyloxy), Boc or BOC (tert-butoxycarbonyl), and Su or Suc(succinimide). For greater certainty, other examples of abbreviationsinclude 1,3PDS (1,3-propanedisulfonic acid), MeOH (methanol), EtOH(ethanol), Et₂O (diethyl ether), CH₂Cl₂ (dichloromethane), CH₂I₂(diiodomethane), CH₃CN or MeCN (acetonitrile), H₂O (water), THF(tetrahydrofuran), DMF (N,N-dimethylformamide), HCl (hydrochloric acid),and DBU (1,8-biazabicyclo[5.4.0]undec-7-ene).

The chemical structures herein are drawn according to the conventionalstandards known in the art. Thus, where an atom, such as a carbon atom,as drawn appears to have an unsatisfied valency, then that valency isassumed to be satisfied by a hydrogen atom even though that hydrogenatom is not necessarily explicitly drawn. Hydrogen atoms should beinferred to be part of the compound.

The symbol “—” in general represents a bond between two atoms in thechain. Thus CH₃—O—CH₂—CH(R_(i))—CH₃ represents a2-substituted-1-methoxypropane compound. In addition, the symbol “—”represents the point of attachment of the substituent to a compound.Thus for example —(C₁-C₆)alkylaryl indicates an arylalkyl group, such asbenzyl, attached to the compound through the alkyl moiety. Further, whenpartial structures of the compounds are illustrated, brackets orequivalents indicate the point of attachment of the partial structure tothe rest of the molecule.

Where multiple substituents are indicated as being attached to astructure, it is to be understood that the substituents can be the sameor different. Thus for example “R_(m) optionally substituted with 1, 2or 3 R_(q) groups” indicates that R_(m) is substituted with 1, 2, or 3R_(q) groups where the R_(q) groups can be the same or different.

As used herein, the terms “compounds of the present invention”,“prodrugs of the present invention” and equivalent expressions refer tocompounds mentioned herein as being useful for at least one purpose ofthe invention, e.g., those encompassed by structural Formulae such as(I), (II), (II-A), (III), (III-A), (IV) and (V) optionally withreference to any of the applicable embodiments of Formulae (B) to (F),and includes specific compounds mentioned herein such as, for example,Compounds A1-A73, B1-B87, C1-C3, D1-D8, G1-G4, N1-N18, and P1, as wellas their pharmaceutically acceptable salts and solvates when applicable.Reference to specific salts in the examples is made by the addition ofthe counterion in brackets (e.g. Compound B51(2TFA) is understood as thebis-trifluoroacetic acid salt of Compound D51). Embodiments herein mayexclude one or more of the compounds of the invention. Compounds may beidentified either by their chemical structure and/or chemical name. Whenthe chemical structure and chemical name conflict, the chemicalstructure is determinative of the identity of the compound.

The term compounds of the invention, unless otherwise noted, alsoencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure, or diastereomerically pure)and enantiomeric and stereoisomeric mixtures if applicable. Enantiomericand stereoisomeric mixtures can be resolved into their componentenantiomers or stereoisomers using separation techniques or chiralsynthesis techniques well known to the skilled artisan, e.g., chiralchromatography (such as chiral HPLC), immunoassay techniques, or the useof covalently (such as Mosher's esters) and non-covalently (such aschiral salts) bound chiral reagents to respectively form adiastereomeric mixture which can be separated by conventional methods,such as chromatography, distillation, crystallization or sublimation,the chiral salt or ester is then exchanged or cleaved by conventionalmeans, to recover the desired isomers. The compounds may also exist inseveral tautomeric forms including the enol form, the keto form, andmixtures thereof. Accordingly, the term also encompass all possibletautomeric forms of the illustrated compounds. The term also includeisotopically labeled compounds where one or more atoms have an atomicmass different from the atomic mass most abundantly found in nature.Examples of isotopes that may be incorporated into the compounds of thepresent invention include, but are not limited to, ²H (D), ³H (T), ¹¹C,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, any one of the isotopes of sulfur, etc.Compounds may exist in unsolvated forms as well as solvated forms,including hydrated forms. Certain compounds may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated herein and are intended to bewithin the scope of the present invention, and are intended to beincluded by the term “compounds of the invention” and equivalents.

The term “prodrug” and equivalent expressions refer to agents which canbe converted in vitro or in vivo directly or indirectly to an activeform (see, e.g., R. B. Silverman, 1992, “The Organic Chemistry of DrugDesign and Drug Action,” Academic Press, Chap. 8; Bundgaard, Hans;Editor. Neth. (1985), “Design of Prodrugs”. 360 pp. Elsevier, Amsterdam;Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J.(Eds.) (2007), “Prodrugs: Challenges and Rewards, XVIII, 1470 p.Springer). Prodrugs can be used to alter the biodistribution (e.g., toallow agents which would not typically enter the reactive site of theprotease) or the pharmacokinetics for a particular agent. A wide varietyof groups have been used to modify compounds to form prodrugs, forexample, esters, ethers, phosphates, etc. When the prodrug isadministered to a subject, the group is cleaved, enzymatically ornon-enzymatically, reductively, oxidatively, or hydrolytically, orotherwise to reveal the active form. Prodrugs are frequently, althoughnot necessarily, pharmacologically inactive until converted to theparent drug.

The term “oligomer” or “gemini dimer” and equivalent expressions referto a synthetic compound comprising at least two moieties of the sameagent or drug coupled together. For background on gemini dimers, see:Hammell D C, Hamad M, Vaddi H K, Crooks P A, Stinchcomb A L, A duplex“Gemini” prodrug of naltrexone for transdermal delivery, J ControlRelease, 2004, 97(2):283-90. In preferred embodiment, the gemini dimersof the invention are made of two linked 1,3PDS molecules that may beconverted in vitro or in vivo directly or indirectly to release at leastone, preferably two, pharmaceutically active 1,3PDS molecules.

The term “ester” refers to compounds that can be represented by theformula RCOOR (carboxylic ester) or the formula RSO₃R′ (sulfonateester), where the group R can be, for example 1,3PDS or the3-sulfopropane part thereof, and the group R′ is another organic group.These compounds are usually respectively formed by the reaction betweena carboxylic or a sulfonic acid and an alcohol usually with theelimination of water, or by the reaction of an activated form of thecarboxylic or sulfonic acid with an alcohol. The term “sulfonate ester”refers to an esterified sulfonic acid, and which are represented, forexample, by the compounds of Formulae II and II-A.

The term “amino acid” generally refers to an organic compound comprisingboth a carboxylic acid group and an amine group. The term “amino acid”includes both “natural” and “unnatural” or “non-natural” amino acids.Additionally, the term amino acid includes O-alkylated or N-alkylatedamino acids, as well as amino acids having nitrogen or oxygen-containingside chains (such as Lys, Orn, or Ser) in which the nitrogen or oxygenatom has been acylated or alkylated. Amino acids may be pure L or Disomers or mixtures of L and D isomers, including racemic mixtures.Amino acid may be α-, or β-, or γ-, or δ-, or ω-amino acid.

The term “natural amino acid” and equivalent expressions refer toL-amino acids commonly found in naturally occurring proteins. Examplesof natural amino acids include, without limitation, alanine (Ala),cystein (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine(Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys),leucine (Leu), methionine (Met), asparagine (Asp), proline (Pro),glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine(Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), andγ-aminobutyric acid (GABA).

The term “unnatural amino acid” refers to any derivative of a naturalamino acid including D forms, and α- and β-amino acid derivatives. Theterms “unnatural amino acid” and “non-natural amino acid” are usedinterchangeably herein and are meant to include the same moieties. It isnoted that certain amino acids, e.g., hydroxyproline, that areclassified as a non-natural amino acid herein, may be found in naturewithin a certain organism or a particular protein. Amino acids with manydifferent protecting groups appropriate for immediate use in the solidphase synthesis of peptides are commercially available. In addition tothe twenty most common naturally occurring amino acids, the followingexamples of non-natural amino acids and amino acid derivatives may beused according to the invention (common abbreviations in parentheses):2-aminoadipic acid (Aad), 3-aminoadipic acid (β-Aad), 2-aminobutyricacid (2-Abu), α,β-dehydro-2-aminobutyric acid (8-AU),1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid(Aib), 3-aminoisobutyric acid (β-Aib), 2-amino-thiazoline-4-carboxylicacid, 5-aminovaleric acid (5-Ava), 6-aminohexanoic acid (6-Ahx),2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc),11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado),2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoicacid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (Statine, Sta),aminooxyacetic acid (Aoa), 2-aminotetraline-2-carboxylic acid (ATC),4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA),para-aminophenylalanine (4-NH₂-Phe), 2-aminopimelic acid (Apm),biphenylalanine (Bip), para-bromophenylalanine (4-Br-Phe),ortho-chlorophenylalanine (2-Cl-Phe), meta-chlorophenylalanine(3-Cl-Phe), para-chlorophenylalanine (4-Cl-Phe), meta-chlorotyrosine(3-Cl-Tyr), para-benzoylphenylalanine (Bpa), tert-butylglycine (TLG),cyclohexylalanine (Cha), cyclohexylglycine (Chg), desmosine (Des),2,2-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr),2,4-diaminobutyric acid (Dbu), 3,4-dichlorophenylalanine (3,4-C1₂-Phe),3,4-diflurorphenylalanine (3,4-F₂-Phe), 3,5-diiodotyrosine (3,5-I₂-Tyr),N-ethylglycine (EtGly), N-ethylasparagine (EtAsn),ortho-fluorophenylalanine (2-F-Phe), meta-fluorophenylalanine (3-F-Phe),para-fluorophenylalanine (4-F-Phe), meta-fluorotyrosine (3-F-Tyr),homoserine (Hse), homophenylalanine (Hfe), homotyrosine (Htyr),hydroxylysine (Hyl), allo-hydroxylysine (aHyl), 5-hydroxytryptophan(5-OH-Trp), 3- or 4-hydroxyproline (3- or 4-Hyp), para-iodophenylalanine(4-I-Phe), 3-iodotyrosine (3-I-Tyr), indoline-2-carboxylic acid (Idc),isodesmosine (Ide), allo-isoleucine (a-Ile), isonipecotic acid (Inp),N-methylisoleucine (MeIle), N-methyllysine (MeLys), meta-methyltyrosine(3-Me-Tyr), N-methylvaline (MeVal), 1-naphthylalanine (1-NaI),2-naphthylalanine (2-NaI), para-nitrophenylalanine (4-NO₂-Phe),3-nitrotyrosine (3-NO₂-Tyr), norleucine (Nle), norvaline (Nva),ornithine (Orn), ortho-phosphotyrosine (H₂PO₃-Tyr),octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen),pentafluorophenylalanine (F₅-Phe), phenylglycine (Phg), pipecolic acid(Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine(Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thienylalanine,and thiazolidine-4-carboxylic acid (thioproline, Th).

The term “aliphatic group” includes organic moieties characterized bystraight or branched-chains, typically having between 1 and 16 carbonatoms, or having between 1 to 12, 1 to 8, 1 to 5 or 1 to 3 carbon atoms.Aliphatic groups include acyclic alkyl groups, alkenyl groups, andalkynyl groups.

As used herein, the term “acyclic” refers to an organic moiety withoutring system.

As used herein, the term “alkyl” refers to saturated hydrocarbons havingfrom one to sixteen carbon atoms, including linear or branched alkylgroups. Examples of alkyl groups include, without limitation, methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,isopropyl, tert-butyl, sec-butyl, isobutyl, and the like. The term“C₁-C_(n)alkyl” refers to an alkyl group having from 1 to the indicated“n” number of carbon atoms.

As used herein, the term “alkenyl” refers to unsaturated hydrocarbonshaving from two to sixteen carbon atoms, including linear or branchedalkenyl groups, and comprising between one and six carbon-carbon doublebonds. Examples of alkenyl groups include, without limitation, vinyl,allyl, 1-propen-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-4-yl,1-penten-5-yl, 1,3-pentadien-5-yl, and the like. The term alkenylincludes both unsubstituted alkenyl groups and substituted alkenylgroups. The term “C₂-C_(n)alkenyl” refers to an alkenyl group havingfrom 2 to the indicated “n” number of carbon atoms.

As used herein, the term “alkynyl” refers to unsaturated hydrocarbonshaving from two to twelve carbon atoms, including linear or branchedalkynyl groups, and comprising between one to six carbon-carbon triplebond. Examples of alkynyl groups include, without limitation, ethynyl,1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl, 1-pentyn-5-yl,1,3-pentadiyn-5-yl, and the like. The term alkynyl includes bothunsubstituted alkynyl groups and substituted alkynyl groups. The term“C₂-C_(n)alkynyl” refers to an alkynyl group having from 2 to theindicated “n” number of carbon atoms.

Unless the number of carbons is otherwise specified, “lower” as in“lower aliphatic,” “lower alkyl,” “lower alkenyl,” and “lower alkylnyl”,as used herein means that the moiety has at least one (two for alkenyland alkynyl) and equal or less than 6 carbon atoms.

The terms “cycloalkyl”, “alicyclic”, “carbocyclic” and equivalentexpressions refer to a group comprising a saturated or partiallyunsaturated (non aromatic) carbocyclic ring in a monocyclic orpolycyclic ring system, including spiro (sharing one atom) or fused(sharing at least one bond) carbocyclic ring systems, having from threeto fifteen ring members. Examples of cycloalkyl groups include, withoutlimitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl,cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl,cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl,norbornyl, and the like. The term cycloalkyl includes both unsubstitutedcycloalkyl groups and substituted cycloalkyl groups. The term“C₃-C_(n)cycloalkyl” refers to a cycloalkyl group having from 3 to theindicated “n” number of carbon atoms in the ring structure. Unless thenumber of carbons is otherwise specified, “lower cycloalkyl” groups asherein used, have at least 3 and equal or less than 8 carbon atoms intheir ring structure.

The term “heterocycloalkyl” and equivalent expressions refer to a groupcomprising a saturated or partially unsaturated (non aromatic)carbocyclic ring in a monocyclic or polycyclic ring system, includingspiro (sharing one atom) or fused (sharing at least one bond)carbocyclic ring systems, having from three to fifteen ring members,where one or more (up to six) ring members are substituted orunsubstituted heteroatoms (e.g. N, O, S, P) or groups containing suchheteroatoms (e.g. NH, NR_(x) (R_(x) is alkyl, acyl, aryl, heteroaryl orcycloalkyl), PO₂, SO, SO₂, and the like). Heterocycloalkyl groups may beC-attached or heteroatom-attached (e.g. via a nitrogen atom) where suchis possible. Examples of heterocycloalkyl groups include, withoutlimitation, pyrrolidino, tetrahydrofuranyl, tetrahydrodithienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3,1,0]hexanyl,3-azabicyclo[4,1,0]heptanyl, quinolizinyl, and sugars, and the like. Theterm heterocycloalkyl includes both unsubstituted heterocycloalkylgroups and substituted heterocycloalkyl groups. The term“C₃-C_(n)heterocycloalkyl” refers to a heterocycloalkyl group havingfrom 3 to the indicated “n” number of atoms (carbon or heteroatom orgroup) in the ring structure, including at least one hetero group oratom as defined above. Unless the number of carbons is otherwisespecified, “lower heterocycloalkyl” groups as herein used, have at least3 and equal or less than 8 ring members in their ring structure.

The terms “aryl” and “aryl ring” refer to aromatic groups having 4n+2π(pi) electrons, wherein n is an integer from 1 to 3, in a conjugatedmonocyclic or polycyclic system (fused or not) and having six tofourteen ring atoms. A polycyclic ring system includes at least onearomatic ring. Aryl may be directly attached, or connected via aC₁-C₃alkyl group (also referred to as arylalkyl or aralkyl). Examples ofaryl groups include, without limitation, phenyl, benzyl, phenetyl,1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl,benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthylenyl,fluorenyl, phenanthernyl, anthracenyl, and the like. The term arylincludes both unsubstituted aryl groups and substituted aryl groups. Theterm “C₆-C_(n)aryl” refers to an aryl group having from 6 to theindicated “n” number of carbons in the ring structure.

The terms “heteroaryl” and “heteroaryl ring” refer to aromatic groupshaving 4n+2 π(pi) electrons, wherein n is an integer from 1 to 3, in aconjugated monocyclic or polycyclic system (fused or not) and havingfive to fourteen ring members, including one to six substituted orunsubstituted heteroatoms (e.g. N, O, S) or groups containing suchheteroatoms (e.g. NH, NR_(x) (R_(x) is alkyl, acyl, aryl, heteroaryl orcycloalkyl), SO, and the like). A polycyclic ring system includes atleast one heteroaromatic ring. Heteroaryls may be directly attached, orconnected via a C₁-C₃alkyl group (also referred to as heteroarylalkyl orheteroaralkyl). Heteroaryl groups may be C-attached orheteroatom-attached (e.g. via a nitrogen atom), where such is possible.Examples of heteroaryl groups include, without limitation, pyridyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furyl,thienyl; isooxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrollyl,quinolinyl, isoquinolinyl, indolyl, 3H-indolyl, indolinyl, isoindolyl,chromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl,indazolyl, indolizinyl, phthalazinyl, pyridazinyl, pyrazinyl, triazinyl,isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothienyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinolizinyl, quinolonyl, isoquinolonyl,quinoxalinyl, naphthyridinyl, furopyridinyl, carbazolyl,phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxazinyl, dibenzofurnayl, and the like. The termheteroaryl includes both unsubstituted heteroaryl groups and substitutedheteroaryl groups. The term “C₅-C_(n)heteroaryl refers to an heteroarylgroup having from 5 to the indicated “n” number of atoms (carbon orheteroatom or group) in the ring structure, including at least onehetero group or atom as defined above.

The terms “heterocycle” or “heterocyclic” or “heterocyclyl” includeheterocycloalkyl and heteroaryl groups. Examples of heterocyclesinclude, without limitation, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, carbazolyl, 4αH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,xanthenyl, and the like. The term heterocycle includes bothunsubstituted heterocyclic groups and substituted heterocyclic groups.

The term “amine” or “amino,” as used herein, refers to an unsubstitutedor substituted moiety of the formula —NR^(a)R^(b), in which R^(a) andR^(b) are each independently hydrogen, alkyl, aryl, or heterocyclyl, orR^(a) and R^(b), taken together with the nitrogen atom to which they areattached, form a heterocyclic ring. The term “aminocarbonyl” includescompounds or moieties which contain a nitrogen atom bound to the carbonof a carbonyl or a thiocarbonyl group. The term acylamino refers to anamino group directly attached to an acyl group as defined herein.

The term “nitro” means —NO₂; the terms “halo” and “halogen” refer tobromine, chlorine, fluorine or iodine substituents; the term “thiol”,“thio”, or “mercapto” means SH; and the term “hydroxyl” or “hydroxy”means —OH. The term “alkylthio” refers to an alkyl group, having asulfhydryl group attached thereto. Suitable alkylthio groups includegroups having 1 to about 12 carbon atoms, preferably from 1 to about 6carbon atoms. The term “alkylcarboxyl” as used herein means an alkylgroup having a carboxyl group attached thereto.

The term “alkoxy” or “lower alkoxy” as used herein means an alkyl grouphaving an oxygen atom attached thereto. Representative alkoxy groupsinclude groups having 1 to about 6 carbon atoms, e.g., methoxy, ethoxy,propoxy, tert-butoxy and the like. Examples of alkoxy groups includemethoxy, ethoxy, isopropyloxy, propoxy, butoxy, pentoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy,trichloromethoxy groups and the like. The term alkoxy includes bothunsubstituted or substituted alkoxy groups, etc., as well as halogenatedalkyloxy groups.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom.Examples of moieties which contain a carbonyl include aldehydes,ketones, carboxylic acids, amides, esters, anhydrides, etc.

The term “acyl” refers to a carbonyl group that is attached through itscarbon atom to a hydrogen (i.e., formyl), an aliphatic group(C₁-C_(n)alkyl, C₁-C_(n)alkenyl, C₁-C_(n)alkynyl, wherein n is aninteger from 2 to 10; e.g. acetyl, a cycloalkyl group (e.g.C₃-C₈cycloalkyl), a heterocyclic group (e.g. C₃-C₈heterocycloalkyl andC₅-C₆heteroaryl), an aromatic group (e.g. C₆aryl, e.g., benzoyl), andthe like. Acyl groups may be unsubstituted or substituted acyl groups(e.g. salicyloyl).

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance with thepermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. As used herein, the term “substituted” ismeant to include all permissible substituents of organic compounds. In abroad aspect, the permissible substituents include acyclic and cyclic,branched and unbranched, carbocyclic and heterocyclic, aromatic andnonaromatic substituents of organic compounds. The permissiblesubstituents can be one or more. The term “substituted”, when inassociation with any of the foregoing groups refers to a groupsubstituted at one or more position with substituents such as acyl,amino (including simple amino, mono and dialkylamino, mono anddiarylamino, and alkylarylamino), acylamino (including carbamoyl, andureido), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,alkoxycarbonyl, carboxy, carboxylate, aminocarbonyl, mono anddialkylaminocarbonyl, cyano, azido, halogen, hydroxyl, nitro,trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl,thiocarboxylate, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, lower alkoxy, aryloxy,aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl, alkylsulfinyl,sulfonyl, sulfate, sulfonate, sulfonamide, phosphate, phosphonato,phosphinato, oxo, guanidine, imino, formyl and the like. Any of theabove substituents can be further substituted if permissible, e.g. ifthe group contains an alkyl group, an aryl group, or other.

The term “solvate” refers to a physical association of a compound ofthis invention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances, the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates,iso-propanolates, 1-butanolates, 2-butanolate, and solvates of otherphysiologically acceptable solvents, such as the Clas 3 solventsdescribed in the International Conference on Harmonization (ICH), Guidefor Industry, Q3C Impurities: Residual Solvents (1997). The compounds ofthe invention include each solvate and mixtures thereof.

A “pharmaceutically acceptable salt” of a compound and equivalentexpressions, means a salt of a compound that is pharmaceuticallyacceptable. Desirable are salts of a compound that retain or improve thebiological effectiveness and properties of the free acids and bases ofthe parent compound as defined herein or that takes advantage of anintrinsically basic, acidic or charged functionality on the molecule andthat is not biologically or otherwise undesirable. Example ofpharmaceutically acceptable salts are also described, for example, inBerge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 66, 1-19 (1977).Such salts include:

(1) acid addition salts, formed on a basic or positively chargedfunctionality, by the addition of inorganic acids such as hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid,nitric acid, phosphoric acid, carbonate forming agents, and the like; orformed with organic acids such as acetic acid, propionic acid, lacticacid, oxalic, glycolic acid, pivalic acid, t-butylacetic acid,β-hydroxybutyric acid, valeric acid, hexanoic acid,cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, cyclohexylaminosulfonic acid,benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid,2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid,3-phenyl propionic acid, lauryl sulphonic acid, lauryl sulfuric acid,oleic acid, palmitic acid, stearic acid, lauric acid, embonic (pamoic)acid, palmoic acid, pantothenic acid, lactobionic acid, alginic acid,galactaric acid, galacturonic acid, gluconic acid, glucoheptonic acid,glutamic acid, naphthoic acid, hydroxynapthoic acid, salicylic acid,ascorbic acid, stearic acid, muconic acid, and the like;

(2) base addition salts, formed when an acidic proton present in theparent compound either is replaced by a metal ion, including, an alkalimetal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g.magnesium, calcium, barium), or other metal ions such as aluminum, zinc,iron, vanadium and the like; or coordinates with an organic base such asammonia, ethylamine, diethylamine, ethylenediamine,N,N′-dibenzylethylenediamine, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, piperazine,chloroprocain, procain, choline, lysine and the like.

Pharmaceutically acceptable salts may be synthesized from the parentagent that contains a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts are prepared by reacting the free acid orbase forms of these agents with a stoichiometric amount of theappropriate base or acid in water or in an organic solvent, or in amixture of the two. Salts may be prepared in situ, during the finalisolation or purification of the agent or by separately reacting apurified compound of the invention in its free acid or base form withthe desired corresponding base or acid, and isolating the salt thusformed. The term “pharmaceutically acceptable salts” also includezwitterionic compounds containing a cationic group covalently bonded toan anionic group, as they are “internal salts”.

All acid, salt, base, and other ionic and non-ionic forms of thecompounds described are included as compounds of the invention. Forexample, if a compound is shown as an acid herein, the salt forms of thecompound are also included. Likewise, if a compound is shown as a salt,the acid and/or basic forms are also included.

“AUC” is the area under a curve representing the concentration of acompound in a biological sample of a subject as a function of timefollowing administration of the compound to the subject. Examples ofbiological samples include biological fluids such as plasma and blood,or organ homogenates such as brain or liver homogenates. The AUC can bedetermined by measuring the concentration of a compound in a biologicalsample such as the plasma, blood or brain homogenate using methods suchas liquid chromatography-tandem mass spectrometry (LC/MS/MS), at varioustime intervals, and calculating the area under theconcentration-versus-time curve. Suitable methods for calculating theAUC from a drug concentration-versus-time curve are well known in theart. As relevant to the disclosure here, an AUC for 1,3PDS can bedetermined by measuring the concentration of 1,3PDS in the plasma, bloodor brain homogenate of a subject following oral administration of acompound of the invention to the subject. Unless noted otherwise herein;AUC means AUC_(0-∞).

“Bioavailability” refers to the rate and amount of a drug that reachesthe systemic circulation of a subject following administration of thedrug or prodrug thereof to the patient and can be determined byevaluating, for example, the plasma or blood concentration-versus-timeprofile for the drug. Parameters useful in characterizing a plasma orblood concentration-versus-time curve include the area under the curve(AUC), the time to peak concentration (T_(max)), and the maximum drugconcentration (C_(max)). Bioavailability is often expressed as F(%)referring to the ratio in percentage of the AUC of the compound for aspecific mode of administration (e.g. orally) over AUC of the compoundafter an IV administration. “C_(max)” is the maximum concentration of adrug in the biological sample of a subject following administration of adose of the drug or prodrug to the subject. “T_(max)” is the time to themaximum concentration (C_(max)) of a drug in the biological sample of asubject following administration of a dose of the drug or prodrug to thesubject.

“Bioequivalence” refers to equivalence of the rate and extent ofabsorption of a drug after administration of equal doses of the drug orprodrug to a patient. As used herein, two plasma or blood concentrationprofiles are bioequivalent if the 90% confidence interval for the ratioof the mean response of the two profiles is within the limits of 0.8 and1.25. The mean response includes at least one of the characteristicparameters of a profile such as C_(max), T_(max), and AUC.

As used herein the term “effective amount” refers to the amount or doseof the compound, upon single or multiple dose administration to thepatient, which provides the desired effect in the patient underdiagnosis or treatment. An effective amount can be readily determined bythe attending diagnostician, as one skilled in the art, by the use ofknown techniques and by observing results obtained under analogouscircumstances. In determining the effective amount or dose of compoundadministered, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the size, age, and generalhealth of the subject; the specific disease involved; the degree of orinvolvement or the severity of the disease; the response of theindividual subject; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

As used herein the term “therapeutic bio-distribution of 1,3PDS” refersto one or more pharmacokinetic parameters of 1,3PDS which affect 1,3PDStherapeutic activity. Examples of such pharmacokinetic (PK) parametersinclude but are not limited to: bioavailability of 1,3PDS, AUC of1,3PDS, C_(max) of 1,3PDS, T_(max) of 1,3PDS, bio-absorption of 1,3PDS,bio-distribution of 1,3PDS etc.

As used herein the terms “increased (or like terms, e.g., increasing,increase in, etc.) therapeutic effectiveness of 1,3PDS” and “enhanced(or like terms, e.g., enhancing, enhancement, etc.) therapeuticeffectiveness of 1,3PDS” refer to an increased effectiveness of 1,3PDSas measured, e.g., by one or more parameters listed under “therapeuticbio-distribution of 1,3PDS” above, e.g., by 5%, 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95%, 99%, 125%, etc., or even more, e.g., 2, or 4fold, or even more when administered to a subject, e.g., animal orhuman, which increase is with respect to the same equivalent molar doseof 1,3PDS administered orally in water solution.

The term “reduction of side effects of 1,3PDS” refers to decreasing theamount of or severity of one or more side effects of 1,3PDS by, e.g.,5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9%, oreven 100%, which decrease is with respect to the amount of or severityof a side effect of 1,3PDS that is exhibited when the same equivalentmolar dose of free or disodium salt of 1,3PDS is administered orally.

The term “reduction of effective dosage of 1,3PDS” refers to decreasingthe molar amount of 1,3PDS in the prodrug necessary to be administeredto achieve the same or equivalent result as achieved by administeringfree 1,3PDS (e.g. to achieve equivalent parameters such as one of AUC,C_(max), T_(max), % F, an the like). The decrease is for exampleadministration of 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, of thedose of 1,3PDS (molar equivalent) in order to achieve the same orequivalent blood levels as compared to administration of free 1,3PDS, orto reach equivalent efficacy.

More generally, the terms lessening etc., increasing etc., refer incontext herein to the percentage changes, e.g., by 5%, 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 125%, etc., or even more, e.g.,2, or 4 fold, or even more.

When referring to “1,3PDS” being produced (e.g., released from aformulation or prodrug), all forms of 1,3PDS are included, e.g.,solvates thereof, ionically dissociated forms thereof, charged formsthereof, etc.

“Pharmaceutically acceptable” and equivalent expressions refer to salts,drugs, medicaments, inert ingredients, carrier, vehicle, fillers, etc.,which the term describes, suitable for use in contact with the tissuesof humans and lower animals without undue toxicity, incompatibility,instability, irritation, allergic response, and the like, commensuratewith a reasonable benefit/risk ratio. It preferably refers to a compoundor composition that is approved or approvable by a regulatory agency ofthe Federal or state government or listed in the U.S. Pharmacopoeia orother generally recognized pharmacopoeia for use in animals and moreparticularly in humans.

“Pharmaceutical composition” refers to at least one compound and atleast one pharmaceutically acceptable vehicle, with which the compoundis administered to a subject.

“Pharmaceutically acceptable vehicle” and equivalent expressions referto a diluent, adjuvant, excipient, or carrier with which a compound isadministered.

Reference will now be made in detail to certain embodiments of compoundsand methods. The disclosed embodiments are not intended to be limitingof the invention.

II. Compounds of the Invention

The present invention relates to methods, compounds and compositions fordelivering in a subject, preferably a human subject,1,3-propanedisulfonic acid, or salts thereof, also referred herein as1,3PDS. The invention encompasses compounds that will yield or generate1,3PDS, either in vitro or in vivo.

Accordingly, the invention relates to compounds of Formula I:

wherein,

R¹ is selected from OR³, —NHC(O)R⁵, —NHC(NH)NHR⁵, and—NH(C₅-C₁₀heteroaryl);

R² is selected from OR⁴, —NHC(O)R⁵, —NHC(NH)NHR⁵, and—NH(C₅-C₁₀heteroaryl), or R¹ is a covalent bond and R² is selected fromO, OC₁-C₃alkylO, NH, NC(O)R⁵, NC(NH)NHR⁵, and N(C₅-C₁₀heteroaryl) whenR¹ and R² are taken together with their adjacent atoms to form aheterocycle;

R³ is selected from hydrogen and a substituted or unsubstituted groupselected from C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl,C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl, C₆-C₁₅aryl, andC₅-C₁₅heteroaryl;

R⁴ is a substituted or unsubstituted group selected from C₁-C₁₂alkyl,C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl,C₆-C₁₅aryl, and C₅-C₁₅heteroaryl; and

R⁵ is selected from hydrogen and a substituted or unsubstituted groupselected from C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl,C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl, C₆-C₁₅aryl, andC₅-C₁₅heteroaryl;

or a pharmaceutically acceptable salt or solvate thereof.

The invention pertains to both salt forms and free acid/base forms ofthe compounds of the invention. For example, the invention pertains notonly to the particular salt forms of compounds shown herein as salts,but also the invention includes other pharmaceutically acceptable salts,and the acid and/or base form of the compound. The invention alsopertains to salt forms of compounds shown herein as free acids or bases.

To avoid any confusion, in this section the exemplary compounds of theinvention are all shown in their free (i.e. free acid or base) form.Reference to specific salts in the examples is made by the addition ofthe counterion in brackets. For example, Compound A29(Na) or CompoundA29(sodium salt) is the sodium salt of Compound A29, and CompoundB51(2TFA) is understood as the bis(trifluoroacetic acid) salt ofCompound B51.

The sulfonate ester moiety, any other pharmacokinetic modulating moietyof the prodrugs, their precursors, as well as combinations thereof, maybe cleaved prior to absorption by the gastrointestinal tract (e.g.,within the stomach or intestinal lumen) and/or after absorption by thegastrointestinal tract (e.g., in intestinal tissue, blood, liver, orother suitable tissue of a mammal). In certain embodiments, 1,3PDSremains covalently attached to the pharmacokinetic modulating moietyduring transit across the intestinal mucosal barrier. In certainembodiments, pharmacokinetic modulating moieties according to theinvention are essentially not metabolized to the corresponding 1,3PDSwithin cells of the intestine or liver (e.g. enterocytes, hepatocytes),but generates the parent 1,3PDS molecule once within the systemiccirculation. These prodrugs may be absorbed into the systemiccirculation either by active transport, passive diffusion, or by acombination of both active and passive processes.

The pharmacokinetic modulating moiety of certain of the compoundsaccording to the invention may be cleaved either chemically and/orenzymatically. One or more enzymes present in the stomach, intestinallumen, intestinal tissue, blood, liver, or any other suitable tissue ororgan of a mammal may enzymatically cleave release 1,3PDS. Thepharmacokinetic moiety may also be cleaved indirectly by the cleavage ofa moiety located, for example, 5 to 7 atoms away from the sulfonateester, the cleavage of said moiety triggering internal cyclization, orother internal reaction, to liberate the desired free drug. Thecleavable moiety will generally comprise a bond which is known to be socleavable such as but not limited to, a peptide, amide, ester, sulfide,disulfide, carboxamate, urea, —N—O—, etc. bond, and others asdemonstrated for example in the structures disclosed herein, all ofwhich are in general applicable as linkages in compounds in general.Actual cleavability of the linker can be assessed in vitro and/or invivo by using hydrolytic-, enzymatic- (e.g. peptidase, esterase) ormetabolic-based tests and assays well known in the art. InternationalPCT application WO 91/14434, WO 96/18609, published applications US2005/0096317, and US 2006/0046967, and Yan L. et al, (2004), J. Med.Chem., 47, 1031-43, are all incorporated herein by reference in theirentirety since they describe a variety of linkers that may be usefulaccording to the present invention.

Although theory of operation is discussed herein, for specific compoundstructures, including all generic structural formulas and specific namesand formulas of compounds, the invention is not limited by any suchtheories unless specifically stated otherwise. Thus, all uses of allnovel compounds are encompassed by the invention, irrespective ofmechanism or theory of operation.

A. The Sulfonate Ester Prodrugs:

The invention also relates to a compound of the Formula II:

wherein,

R³ is selected from hydrogen and a substituted or unsubstituted groupselected from C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl,C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl, C₆-C₁₅aryl, andC₅-C₁₅heteroaryl; and

R⁴ is a substituted or unsubstituted group selected from C₁-C₁₂alkyl,C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl,C₆-C₁₅aryl, and C₅-C₁₅heteroaryl; or a pharmaceutically acceptable saltor solvate thereof.

The invention also relates to compounds of Formula II, wherein at leastone of R³ or R⁴ is a pharmacokinetic modulating moiety. Examples ofsuitable pharmacokinetic modulating moieties include sulfonate esters,neopentyl sulfonate esters, aryl sulfonate ester, and nitro-substitutedaryl sulfonate esters.

In another aspect, the invention relates to Formula II-A, as well assalts and solvates thereof:

wherein,

R⁴ is a substituted or unsubstituted group selected from C₁-C₁₂alkyl,C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl,C₆-C₁₅aryl, and C₅-C₁₅heteroaryl; or a pharmaceutically acceptable saltor solvate thereof.

The invention also relates to compounds of Formula II or II-A, whereinR³ and/or R⁴ are each independently selected from the group consistingof: (i) a substituted or unsubstituted group selected from C₁-C₁₂alkyl,C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl,C₆-C₁₅aryl, and C₅-C₁₅heteroaryl; (ii) a substituted or unsubstitutedgroup selected from C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₆-C₁₅aryl, andC₅-C₁₅heteroaryl; (iii) a substituted or unsubstituted group selectedfrom C₃-C₈alkyl, C₆-C₁₀aryl, and C₅-C₁₀heteroaryl; (iv) a substituted orunsubstituted C₁-C₁₂alkyl group; (v) a substituted C₃-C₈alkyl group;(vi) a branched C₃-C₈alkyl group; (vii) a substituted branchedC₃-C₈alkyl group; (viii) a substituted or unsubstituted neopentyl group;(ix) a substituted neopentyl group; or (x) a group of Formula B:

wherein,

R⁶, R⁷ and R⁸ are each independently a substituted or unsubstitutedgroup selected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, C₆-C₁₀aryl, C₅-C₁₀heteroaryl,C(O)OH, C(O)OC₁-C₆alkyl, NH₂, NHC(O)OC₁-C₆alkyl, or R⁷ and R⁸ are takentogether with their adjacent carbon atom to form a group selected fromC₃-C₈cycloalkyl, and C₃-C₈heterocycloalkyl, or R⁶, R⁷ and R⁸ are takentogether with their adjacent carbon atom to form a C₄-C₁₀cycloalkyl orC₄-C₁₀heterocycloalkyl fused ring group, or a C₆-C₁₀aryl, andC₆-C₁₀heteroaryl; and

R²² is a hydrogen atom or a group selected from C₁-C₆alkyl, C(O)OH, orC(O)OC₁-C₆alkyl.

According to one aspect, at least one of R³ and/or R⁴ in Formula II orII-A is the group of Formula B, wherein R²² is C₂-C₆alkyl, wherein R²²is a C₃-C₅alkyl, or wherein R²² is a C₃-C₄alkyl. According to anotheraspect, at least one of R³ and/or R⁴ in Formula II or II-A is a group ofFormula Formula B′ defined as follows:

wherein,

-   -   R⁶, R⁷ and R⁸ are as previously defined.

More particularly, the invention relates to compounds of Formula II orII-A, wherein R³ and/or R⁴ are each independently a group of Formula Bor B′, wherein R⁶ is —CH₂CH₂Nu or —CH₂Nu, wherein Nu is a nucleophilicgroup, which is a functional group having a reactive pair of electronsand having the ability of forming a chemical bond by donating electrons.For example, the nucleophilic group is selected from the groupconsisting of carboxylates, sulfonates, substituted or unsubstitutedamines, alcohols (hydroxyl), thiols, sulfides, hydroxylamines, andimines. In another embodiment, the nucleophilic group is selected fromthe group consisting of substituted or unsubstituted amines, andalcohols (hydroxyl), preferably an unsubstituted amine (NH₂). Theinvention also further relates to compounds of Formula II or II-A,wherein R⁴ is a group of Formula B or B′, wherein R⁶ is —CH₂CH₂NH₂, andR⁷ and R⁸ are each independently a substituted or unsubstituted groupselected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C₃-C₆heterocycloalkyl, C₆-C₁₀aryl, and C₅-C₁₀heteroaryl, or R⁷ and R⁸are taken together with their adjacent carbon atom to form a groupselected from C₃-C₈cycloalkyl and C₃-C₈heterocycloalkyl. Also, R⁴ may bea group of Formula B or B′ wherein R⁶ is —CH₂CH₂NH(aa)₁₋₃, wherein aa isindependently in each occurence, the residue of a C-coupled amino acid,and R⁷ and R⁸ are each independently a substituted or unsubstitutedgroup selected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, C₆-C₁₀aryl, andC₅-C₁₀heteroaryl, or R⁷ and R⁸ are taken together with their adjacentcarbon atom to form a group selected from C₃-C₈cycloalkyl andC₃-C₈heterocycloalkyl. In a further aspect, R⁴ is a group of Formula Bor B′ wherein R⁶ is —CH₂CH₂NH₂, and R⁷ and R⁸ are each independently aC₁-C₆alkyl, or R⁷ and R⁸ are taken together with their adjacent carbonatom to form a C₃-C₈cycloalkyl, preferably R⁷ and R⁸ are each a methylgroup. In yet another aspect, R⁴ is a group of Formula B or B′ whereinR⁶ is —CH₂CH₂NH(aa), wherein aa is the residue of a C-coupled aminoacid, and R⁷ and R⁸ are each independently a C₁-C₆alkyl, or R⁷ and R⁸are taken together with their adjacent carbon atom to form aC₃-C₈cycloalkyl, preferably R⁷ and R⁸ are each a methyl group. In afurther aspect, R⁷ and R⁸ are taken together with their adjacent carbonatom to form a C₃-C₈heterocycloalkyl, or R⁷ and R⁸ are taken togetherwith their adjacent carbon atom to form a lactone (e.g. a furanone). Inyet a further aspect, R⁶ is a methyl group and R⁷ and R⁸ are takentogether with their adjacent carbon atom to form aC₃-C₈heterocycloalkyl, or R⁷ and R⁸ are taken together with theiradjacent carbon atom to form a lactone (e.g. a furanone).

The invention also relates to compounds of Formula II or II-A, whereinR³ and/or R⁴ are each independently a group of Formula B or B′, whereinR⁶ is a group of Formula C:

wherein,

R⁹ is, separately in each occurrence, selected from hydrogen, hydroxyl,halogen, cyano, trifluoromethyl, nitro, and a substituted orunsubstituted group selected from C₁-C₆alkyl, C₃-C₆cycloalkyl,C₃-C₆heterocycloalkyl, C₆aryl, C₅-C₆heteroaryl, C(O)OH, C(O)OR¹¹, OR¹¹,OC(O)R¹¹, OC(O)OR¹¹, NHC(O)R¹¹, NH₂, NHR¹¹, and N(R¹¹)₂;

X is selected from the group consisting of OH, NH₂, NO₂, CN, SH, C(O)OH,C(O)OR¹², OC(O)OR¹², NHC(O)OR¹², SC(O)OR¹², P(O)(OH)₂, P(O)(OR¹²)₂,P(O)(OR¹²)(OH), OC(O)R¹³, OC(O)NHR¹³, SC(O)R¹³, C(O)R¹⁴, and NHR¹⁵;

n is an integer selected from 0, 1, 2 and 3;

R¹¹ is a substituted or unsubstituted group selected from C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, C₆aryl, C₅-C₆heteroaryl andbenzyl;

R¹² is a substituted or unsubstituted group selected from C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, C₆aryl, C₅-C₆heteroaryl, benzyl,CH₂R¹⁶, and CH(C₁-C₆alkyl)R¹⁶;

R¹³ is a substituted or unsubstituted group selected from C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, C₆aryl, C₅-C₆heteroaryl, andbenzyl;

R¹⁴ is the residue of a natural or unnatural N-coupled amino acid havingan protected or unprotected carboxyl end;

R¹⁵ is the residue of a natural or unnatural C-coupled amino acid havingan protected or unprotected amino end; and

R¹⁶ is selected from the group consisting of OC(O)C₁-C₆alkyl andOC(O)OC₁-C₆alkyl.

The invention also relates to compounds of Formula II or II-A, whereinR³ and/or R⁴ are each independently a group of Formula B or B′, whereinR⁶ is a group of Formula C, wherein R⁹ is selected from hydrogen,hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹, and all othergroups are as previously defined. In one example, R⁹ is selected fromhydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹. Inanother example, R⁹ is selected from hydrogen, hydroxyl, C₁-C₆alkyl,OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹. In another example, R⁹ is selected fromhydroxyl, OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹. According to a further example,R⁹ is hydroxyl and all other groups are as previously defined. In yetanother example, R⁹ is selected from C(O)OH and C(O)OR¹¹.

Another example of compounds of the invention are compounds of FormulaII or II-A, wherein at least one of R³ and R⁴ is a group of Formula B orB′, wherein R⁶ is a group of Formula C, wherein X is selected from OH,NH₂, and SH. In another example, X is selected from C(O)OH, C(O)OR¹²,and C(O)R¹⁴. In another example, X is selected from OC(O)OR¹², OC(O)R¹³,and OC(O)NHR¹³. In another example, X is selected from SC(O)R¹³ and,SC(O)OR¹². In another example, X is selected from NHC(O)OR¹² and NHR¹⁵.In another example, X is selected from OH, OC(O)OR¹², OC(O)R¹³, andOC(O)NHR¹³. In a further example, X is selected from SH, SC(O)R¹³ and,SC(O)OR¹². In yet another example, X is selected from NH₂, NHC(O)OR¹²and NHR¹⁵.

The invention also relates to compounds of Formula II or II-A, whereinR³ and/or R⁴ are each independently a group of Formula B or B′, whereinR⁶ is a group of Formula C, wherein X is C(O)OR¹² and all other groupsare as previously defined. As an example, X is C(O)OR¹², and R¹² isselected from C₁-C₆alkyl, C₆aryl, benzyl, CH₂R¹⁶, and CH(C₁-C₆alkyl)R¹⁶.As another example, X is C(O)OR¹², and R¹² is selected from C₁-C₆alkyl,CH₂R¹⁶, and CH(C₁-C₆alkyl)R¹⁶ and all other groups are as previouslydefined. According to another example, X is C(O)OR¹², R⁹ is selectedfrom hydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹, andall other groups are as previously defined. In a further example, X isC(O)OR¹², R⁹ is selected from hydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹,OC(O)R¹¹, and OC(O)OR¹¹, and R¹² is selected from C₁-C₆alkyl, C₆aryl,benzyl, CH₂R¹⁶, and CH(C₁-C₆alkyl)R¹⁶. In yet another example, X isC(O)OR¹², R⁹ is selected from hydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹,OC(O)R¹¹, and OC(O)OR¹¹, and R¹² is selected from C₁-C₆alkyl, CH₂R¹⁶,and CH(C₁-C₆alkyl)R¹⁶. In one aspect, when X is C(O)OR¹², then n is aninteger selected from 1 or 2, preferably n is 1.

The invention also relates to compounds of Formula II or II-A, whereinR³ and/or R⁴ are each independently a group of Formula B or B′, whereinR⁶ is a group of Formula C and wherein X is NHC(O)OR¹² and all othergroups are as previously defined. As an example, X is NHC(O)OR¹², andR¹² is selected from C₁-C₆alkyl, C₆aryl, benzyl, CH₂R¹⁶, andCH(C₁-C₆alkyl)R¹⁶. In another example, X is NHC(O)OR¹², and R¹² isselected from C₁-C₆alkyl, CH₂R¹⁶, and CH(C₁-C₆alkyl)R¹⁶. According toanother example, X is NHC(O)OR¹², and R⁹ is selected from hydrogen,hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹, and all othergroups are as previously defined. In another example, X is NHC(O)OR¹²,R⁹ is selected from hydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, andOC(O)OR¹¹, and R¹² is selected from C₁-C₆alkyl, C₆aryl, benzyl, CH₂R¹⁶,and CH(C₁-C₆alkyl)R¹⁶. In a further example, X is NHC(O)OR¹², R⁹ isselected from hydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, andOC(O)OR¹¹, and R¹² is selected from C₁-C₆alkyl, CH₂R¹⁶, andCH(C₁-C₆alkyl)R¹⁶. The invention also relates to compounds of Formula IIor II-A, wherein R³ and/or R⁴ are each independently a group of FormulaB or B′, wherein R⁶ is a group of Formula C and wherein n is 2, X isNHC(O)OR¹², and all other groups are as previously defined. As anexample, n is 2, X is NHC(O)OR¹², and R¹² is selected from C₁-C₆alkyl,C₆aryl, benzyl, CH₂R¹⁶, and CH(C₁-C₆alkyl)R¹⁶. In another example, n is2, X is NHC(O)OR¹², and R¹² is selected from C₁-C₆alkyl, CH₂R¹⁶, andCH(C₁-C₆alkyl)R¹⁶. In another example, n is 2, X is NHC(O)OR¹², R¹² isselected from C₁-C₆alkyl, CH₂R¹⁶, and CH(C₁-C₆alkyl)R¹⁶ and R⁹ in atleast one occurrence, is selected from hydroxyl, C₁-C₆alkyl, OR¹¹,OC(O)R¹¹, and OC(O)OR¹¹. In a further example, n is 2, X is NHC(O)OR¹²,R¹² is selected from C₁-C₆alkyl, CH₂R¹⁶, and CH(C₁-C₆alkyl)R¹⁶ and R⁹ inat least one occurrence, is selected from C(O)OH and C(O)OR¹¹. In oneaspect, when X is NHC(O)OR¹², then n is an integer selected from 1 or 2,preferably n is 2.

The invention also relates to compounds of Formula II or II-A, whereinR³ and/or R⁴ are each independently a group of Formula B or B′, whereinR⁶ is a group of Formula C and wherein X is OC(O)R¹³ and all othergroups are as previously defined. For example, X is OC(O)R¹³, and R¹³ isselected from C₁-C₆alkyl, C₆aryl, and benzyl. In another example, X isOC(O)R¹³, and R¹³ is C₁-C₆alkyl. In another example, X is OC(O)R¹³, andR¹³ is C₆aryl. According to another example, X is OC(O)R¹³, and R⁹ isselected from hydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, andOC(O)OR¹¹. In another example, X is OC(O)R¹³, R⁹ is selected fromhydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹, and R¹³is selected from C₁-C₆alkyl, C₆aryl, and benzyl. In another example, Xis OC(O)R¹³, R⁹ is selected from hydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹,OC(O)R¹¹, and OC(O)OR¹¹, and R¹³ is C₁-C₆alkyl. In yet another aspect, Xis OC(O)R¹³, R⁹ is selected from hydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹,OC(O)R¹¹, and OC(O)OR¹¹, and R¹³ is C₆aryl, and all other groups are aspreviously defined. The invention also relates to compounds of FormulaII or II-A, wherein R³ and/or R⁴ are each independently a group ofFormula B or B′, wherein R⁶ is a group of Formula C and wherein n is 2,X is OC(O)R¹³, and all other groups are as previously defined. As anexample, n is 2, X is OC(O)R¹³, and R⁹ in at least one occurrence, isselected from hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹. In afurther example, n is 2, X is OC(O)R¹³, and R⁹ in at least oneoccurrence, is selected from C(O)OH and C(O)OR¹¹. In one aspect, when Xis OC(O)R¹³, then n is an integer selected from 1 or 2, preferably n is2.

The invention also relates to compounds of Formula II or II-A, whereinR³ and/or R⁴ are each independently a group of Formula B or B′, whereinR⁶ is a group of Formula C and wherein X is SH, SC(O)R¹³ or SC(O)OR¹²and all other groups are as previously defined. In one aspect, when X isSH, SC(O)R¹³ or SC(O)OR¹², then n is an integer selected from 1 or 2,preferably n is 2. In another example, n is 2, X is SH, SC(O)R¹³ orSC(O)OR¹², and all other groups are as previously defined. As anotherexample, n is 2, X is SH, SC(O)R¹³ or SC(O)OR¹², and R⁹ in at least oneoccurrence, is selected from hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, andOC(O)OR¹¹. In a further example, n is 2, X is SH, SC(O)R¹³ or SC(O)OR¹²,and R⁹ in at least one occurrence, is selected from C(O)OH and C(O)OR¹¹.

The invention also relates to compounds of Formula II or II-A, whereinR³ and/or R⁴ are each independently a group of Formula B or B′, whereinR⁶ is a group of Formula C and wherein X is NHR¹⁵ and all other groupsare as previously defined. For example, X is NHR¹⁵, and R¹⁵ is theresidue of a natural C-coupled amino acid. In another example, X isNHR¹⁵, and R¹⁵ is the residue of a natural C-coupled hydrophobic aminoacid, such as an aliphatic hydrophobic amino acid (e.g. alanine,isoleucine, leucine, valine and the like), an aromatic hydrophobic aminoacid (e.g. phenylalanine, tryptophan, tyrosine and the like) or a polarhydrophobic amino acid (e.g. cystein, methionine and the like). Inanother example, X is NHR¹⁵, and R¹⁵ is the residue of a naturalC-coupled hydrophilic amino acid (e.g. arginine, lysine, asparagine,histidine, proline, aspartic acid, glutamic acid and the like). Inanother example, X is NHR¹⁵, and R¹⁵ is the residue of a naturalC-coupled neutral polar amino acid (e.g. asparagine, cystein, glutamine,methionine, serine, threonine and the like). In another example, X isNHR¹⁵, and R¹⁵ is the residue of a natural C-coupled acidic amino acid(e.g. aspartic acid, glutamic acid and the like). In yet anotherexample, X is NHR¹⁵, and R¹⁵ is the residue of a natural C-coupled basicamino acid (e.g. arginine, histidine, lysine and the like). According toanother example, X is NHR¹⁵, and R⁹ is selected from hydrogen, hydroxyl,C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹. In another example, X isNHR¹⁵, R⁹ is selected from hydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹,OC(O)R¹¹, and OC(O)OR¹¹, and R¹⁵ is the residue of a natural C-coupledamino acid. In a further example, X is NHR¹⁵, R⁹ is selected fromhydrogen, hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹, and R¹⁵is the residue of a natural C-coupled lipophilic amino acid. In yetanother example, X is NHR¹⁵, R⁹ is selected from hydrogen, hydroxyl,C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, and OC(O)OR¹¹, and R¹⁵ is the residue of anatural C-coupled hydrophilic amino acid. The invention also relates tocompounds of Formula II or II-A, wherein R³ and/or R⁴ are eachindependently a group of Formula B, wherein R⁶ is a group of Formula Cand wherein n is 2, X is NHR¹⁵, and all other groups are as previouslydefined. As an example, n is 2, X is NHR¹⁵, and R⁹ in at least oneoccurrence, is selected from hydroxyl, C₁-C₆alkyl, OR¹¹, OC(O)R¹¹, andOC(O)OR¹¹. In a further example, n is 2, X is NHR¹⁵, and R⁹ in at leastone occurrence, is selected from C(O)OH and C(O)OR¹¹. In one aspect,when X is NHR¹⁵, then n is an integer selected from 1 or 2, preferably nis 2.

Furthermore, the compounds of the invention are encompassed by FormulaII or II-A, wherein R³ and/or R⁴ are each independently a group ofFormula B or B′ and wherein R⁶ is a group of Formula C, and all othergroups are as previously defined. In one example, R⁶ is a group ofFormula C, and R⁷ and R⁸ are each independently a substituted orunsubstituted group selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, C₆-C₁₀aryl, andC₅-C₁₀heteroaryl, or R⁷ and R⁸ are taken together with their adjacentcarbon atom to form a group selected from C₃-C₈cycloalkyl andC₃-C₈heterocycloalkyl. In another example, R⁶ is a group of Formula C,and R⁷ and R⁸ are each independently a C₁-C₆alkyl, or R⁷ and R⁸ aretaken together with their adjacent carbon atom to form aC₃-C₈cycloalkyl, preferably R⁷ and R⁸ are each a methyl group.

The invention also relates to compounds of Formula II or II-A, whereinR³ and/or R⁴ are each independently a substituted or unsubstitutedC₆-C₁₀aryl or C₅-C₁₀heteroaryl. For example, R³ and/or R⁴ are eachindependently a substituted C₆-C₁₀aryl or C₅-C₁₀heteroaryl. In anotherexample, R³ and/or R⁴ are each independently a substituted orunsubstituted C₆aryl or C₅-C₆heteroaryl. In a further example, R³ and/orR⁴ are each independently a group of Formula D:

wherein,

R¹⁷ in each occurrence is each independently a hydrogen atom or asubstituted or unsubstituted group selected from C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl,C₆-C₁₀aryl, C₅-C₁₀heteroaryl, an electron-withdrawing group or asubstituent selected from the group consisting of amino, amido,hydroxyl, alkoxy, acyloxy, alkoxycabonyloxy, and the like; and

m is an integer from 1 to 5.

For example, in Formula II or II-A, where R³ and/or R⁴ are eachindependently a group of Formula D, then R¹⁷ is, in at least oneoccurrence, an electron-withdrawing group, which is a group having theability to attract valence electrons from neighboring atoms. In anotherembodiment, R¹⁷ is an electron-withdrawing group selected from nitro,acyl (ketone), carboxylate (acid), alkoxycarbonyl (ester),alkylaminocarbonyl (amide), formyl (aldehyde), sulfonyl,trifluoromethyl, halogeno (chloro, fluoro, iodo and bromo), and cyanogroups. In another example, R¹⁷ is selected from nitro, acyl (ketone),carboxylate, trifluoromethyl, and halogeno groups (chloro, fluoro, iodoand bromo). In another example, m is an integer selected from 1 to 3,preferably 1 or 2, preferably 1.

The following structures are examples of monosulfonate ester prodrugs ofthe invention and are illustrative of the invention only and they shouldnot be construed as further limiting:

or a pharmaceutically acceptable salt or solvate of any one of CompoundsA1 to A73.

The following structures are examples of disulfonate ester prodrugs ofthe invention and are illustrative of the invention only and they shouldnot be construed as further limiting:

or a pharmaceutically acceptable salt or solvate of any one of CompoundsB1-B87.

In another example, the compound is a compound of Formula I, wherein R¹is a covalent bond, and R² is an oxygen atom, then R¹ and R² takentogether with their adjacent atoms form the 6-membered heterocyclic ringCompound C1.

In yet another example, the compound is a compound of Formula I, whereinR¹ is a covalent bond, and R² is a substituted or unsubstitutedOC₁-C₃alkylO group, and R¹ and R² taken together with their adjacentatoms form an 8 to 10-membered heterocyclic ring. In one embodiment, thecompound is Compound C2.

In another embodiment, the compound is Compound C3

The invention also further relates to a compound of Formula II, whereinat least one of R³ or R⁴ is a group of Formula E:

wherein,

R^(z) is a substituted or unsubstituted group selected from C₁-C₁₂alkyl,C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl,C₆-C₁₅aryl, C₅-C₁₅heteroaryl, OC₁-C₁₂alkyl, OC₂-C₁₂alkenyl,OC₂-C₁₂alkynyl, OC₃-C₁₅cycloalkyl, OC₃—OC₁₅heterocycloalkyl,OC₆-C₁₅aryl, and OC₅-C₁₅heteroaryl.

According to one aspect, the compound of the invention is a compound ofFormula II, and one of R³ or R⁴ is a group of Formula E. In anembodiment of this aspect, R⁴ is Formula E, wherein R^(z) is a groupselected from OC₁-C₆alkyl, C₁-C₆alkyl, C₃-C₇cycloalkyl, or C₆aryl, andR³ is H. In another embodiment, R⁴ is Formula E, wherein R^(z) is agroup selected from OC₁-C₆alkyl, C₁-C₆alkyl, C₃-C₇cycloalkyl, or C₆aryl,and R³ is a group of Formula B. In another embodiment, R⁴ is Formula E,wherein R^(z) is a group selected from OC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₇cycloalkyl, or C₆aryl, and R³ is a group of Formula B, wherein R⁶is a group of Formula C. In another embodiment, R⁴ is Formula E, whereinR^(z) is a group selected from OC₁-C₆alkyl, C₁-C₆alkyl, C₃-C₇cycloalkyl,or C₆aryl, and R³ is a group of Formula B, wherein R⁶ is a group ofFormula C, and wherein X is C(O)OR¹². In another embodiment, R⁴ isFormula E, wherein R^(z) is a C₁-C₆alkyl, and R³ is H. In anotherembodiment, R⁴ is Formula E, wherein R^(z) is a C₁-C₆alkyl, and R³ is agroup of Formula B. In another embodiment, R⁴ is Formula E, whereinR^(z) is a C₁-C₆alkyl, and R³ is a group of Formula B, wherein R⁶ is agroup of Formula C. In another embodiment, R⁴ is Formula E, whereinR^(z) is a C₁-C₆alkyl, and R³ is a group of Formula B, wherein R⁶ is agroup of Formula C, and wherein X is C(O)OR¹². In another embodiment, R⁴is Formula E, wherein R^(z) is a C₂-C₅alkyl, and R³ is H. In anotherembodiment, R⁴ is Formula E, wherein R^(z) is a C₂-C₅alkyl, and R³ is agroup of Formula B. In another embodiment, R⁴ is Formula E, whereinR^(z) is a C₂-C₅alkyl, and R³ is a group of Formula B, wherein R⁶ is agroup of Formula C. In another embodiment, R⁴ is Formula E, whereinR^(z) is a C₂-C₅alkyl, and R³ is a group of Formula B, wherein R⁶ is agroup of Formula C, and wherein X is C(O)OR¹². In another embodiment, R⁴is Formula E, wherein R^(z) is a C₃-C₇cycloalkyl, and R³ is H. Inanother embodiment, R⁴ is Formula E, wherein R^(z) is a C₃-C₇cycloalkyl,and R³ is a group of Formula B. In another embodiment, R⁴ is Formula E,wherein R^(z) is a C₃-C₇cycloalkyl, and R³ is a group of Formula B,wherein R⁶ is a group of Formula C. In another embodiment, R⁴ is FormulaE, wherein R^(z) is a C₃-C₇cycloalkyl, and R³ is a group of Formula B,wherein R⁶ is a group of Formula C, and wherein X is C(O)OR¹². Inanother embodiment, R⁴ is Formula E, wherein R^(z) is a C₅-C₆cycloalkyl,and R³ is H. In another embodiment, R⁴ is Formula E, wherein R^(z) is aC₅-C₆cycloalkyl, and R³ is a group of Formula B. In another embodiment,R⁴ is Formula E, wherein R^(z) is a C₅-C₆cycloalkyl, and R³ is a groupof Formula B, wherein R⁶ is a group of Formula C. In another embodiment,R⁴ is Formula E, wherein R^(z) is a C₅-C₆cycloalkyl, and R³ is a groupof Formula B, wherein R⁶ is a group of Formula C, and wherein X isC(O)OR¹². In another embodiment, R⁴ is Formula E, wherein R^(z) is aC₆aryl, and R³ is H. In further another embodiment, R⁴ is Formula E,wherein R^(z) is a C₆aryl, and R³ is a group of Formula B. In yetanother embodiment, R⁴ is Formula E, wherein R^(z) is a C₆aryl, and R³is a group of Formula B, wherein R⁶ is a group of Formula C. In afurther embodiment, R⁴ is Formula E, wherein R^(z) is a C₆aryl, and R³is a group of Formula B, wherein R⁶ is a group of Formula C, and whereinX is C(O)OR¹².

In another aspect, the compound of the invention is a compound ofFormula II, and R³ and R⁴ are each independently a group of Formula E.In one embodiment of this aspect, R^(z) in each of R³ and R⁴ isindependently a group selected from C₁-C₆alkyl, C₃-C₇cycloalkyl, orC₆aryl. In another embodiment, R^(z) in the group R³ is a group selectedfrom OC₁-C₆alkyl, C₁-C₆alkyl, C₃-C₇cycloalkyl, or C₆aryl, and R^(z) inthe group R⁴ is C₁-C₆alkyl. In another embodiment, R^(z) in the group R³is a group selected from OC₁-C₆alkyl, C₁-C₆alkyl, C₃-C₇cycloalkyl, orC₆aryl, and Fe in the group R⁴ is C₂-C₅alkyl. In another embodiment,R^(z) in the group R³ is a group selected from OC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₇cycloalkyl, or C₆aryl, and R^(z) in the group R⁴ isC₃-C₇cycloalkyl. In another embodiment, R^(z) in the group R³ is a groupselected from OC₁-C₆alkyl, C₁-C₆alkyl, C₃-C₇cycloalkyl, or C₆aryl, andR^(z) in the group R⁴ is C₅-C₆cycloalkyl. In another embodiment, R^(z)in the group R³ is a group selected from OC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₇cycloalkyl, or C₆aryl, and R^(z) in the group R⁴ is C₆aryl. Inanother embodiment, R^(z) in the group R³ is C₁-C₆alkyl, and R^(z) inthe group R⁴ is a group selected from OC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₇cycloalkyl, or C₆aryl. In another embodiment, R^(z) in each of R³and R⁴ is independently a C₁-C₆alkyl group. In another embodiment, R^(z)in the group R³ is C₁-C₆alkyl, and R^(z) in the group R⁴ is C₂-C₅alkyl.In another embodiment, R^(z) in the group R³ is C₁-C₆alkyl, and R^(z) inthe group R⁴ is C₃-C₇cycloalkyl. In another embodiment, R^(z) in thegroup R³ is C₁-C₆alkyl, and Fe in the group R⁴ is C₅-C₆cycloalkyl. Inanother embodiment, R^(z) in the group R³ is C₁-C₆alkyl, and R^(z) inthe group R⁴ is C₆aryl. In another embodiment, R^(z) in the group R³ isC₂-C₅alkyl, and R^(z) in the group R⁴ is a group selected fromOC₁-C₆alkyl, C₁-C₆alkyl, C₃-C₇cycloalkyl, or C₆aryl. In anotherembodiment, R^(z) in the group R³ is C₂-C₅alkyl, and R^(z) in the groupR⁴ is C₁-C₆alkyl. In another embodiment, R^(z) in each of R³ and R⁴ isindependently a C₂-C₅alkyl group. In another embodiment, R^(z) in thegroup R³ is C₂-C₅alkyl, and R^(z) in the group R⁴ is C₃-C₇cycloalkyl. Inanother embodiment, R^(z) in the group R³ is C₂-C₅alkyl, and R^(z) inthe group R⁴ is C₅-C₆cycloalkyl. In another embodiment, R^(z) in thegroup R³ is C₂-C₅alkyl, and R^(z) in the group R⁴ is C₆aryl. In anotherembodiment, R^(z) in the group R³ is C₃-C₇cycloalkyl, and R^(z) in thegroup R⁴ is a group selected from OC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₇cycloalkyl, or C₆aryl. In another embodiment, R^(z) in the group R³is C₃-C₇cycloalkyl, and R^(z) in the group R⁴ is C₁-C₆alkyl. In anotherembodiment, R^(z) in the group R³ is C₃-C₇cycloalkyl, and Fe in thegroup R⁴ is C₂-C₅alkyl. In another embodiment, R^(z) in each of R³ andR⁴ is independently a C₃-C₇cycloalkyl group. In another embodiment,R^(z) in the group R³ is C₃-C₇cycloalkyl, and R^(z) in the group R⁴ isC₅-C₆cycloalkyl. In another embodiment, R^(z) in the group R³ isC₃-C₇cycloalkyl, and R^(z) in the group R⁴ is C₆aryl. In anotherembodiment, R^(z) in the group R³ is C₅-C₆cycloalkyl, and R^(z) in thegroup R⁴ is a group selected from OC₁-C₆alkyl, C₁-C₆alkyl,C₃-C₇cycloalkyl, or C₆aryl. In another embodiment, R^(z) in the group R³is C₅-C₆cycloalkyl, and R^(z) in the group R⁴ is C₁-C₆alkyl. In anotherembodiment, R^(z) in the group R³ is C₅-C₆cycloalkyl, and Fe in thegroup R⁴ is C₂-C₅alkyl. In another embodiment, R^(z) in the group R³ isC₅-C₆cycloalkyl, and R^(z) in the group R⁴ is C₃-C₇cycloalkyl. Inanother embodiment, R^(z) in each of R³ and R⁴ is independently aC₅-C₆cycloalkyl group. In another embodiment, R^(z) in the group R³ isC₅-C₆cycloalkyl, and R^(z) in the group R⁴ is C₆aryl. In anotherembodiment, R^(z) in the group R³ is C₆aryl, and R^(z) in the group R⁴is a group selected from OC₁-C₆alkyl, C₁-C₆alkyl, C₃-C₇cycloalkyl, orC₆aryl. In another embodiment, R^(z) in the group R³ is C₆aryl, andR^(z) in the group R⁴ is C₁-C₆alkyl. In another embodiment, R^(z) in thegroup R³ is C₆aryl, and R^(z) in the group R⁴ is C₂-C₅alkyl. In afurther embodiment, R^(z) in the group R³ is C₆aryl, and R^(z) in thegroup R⁴ is C₃-C₇cycloalkyl. In a further embodiment, R^(z) in the groupR³ is C₆aryl, and R^(z) in the group R⁴ is C₅-C₆cycloalkyl. In yetanother embodiment, R^(z) in each of R³ and R⁴ is independently a C₆arylgroup. In a further embodiment, the compound of the invention isCompound B59, or a pharmaceutically acceptable salt or solvate thereof.

The following structures are examples of sulfonate ester prodrugs of theinvention and are illustrative of the invention only and they should notbe construed as further limiting:

or a pharmaceutically acceptable salt or solvate of any one of CompoundsD1 to D8.

In yet another aspect, the invention further relates to a compound ofFormula II, wherein at least one of R³ or R⁴ is a group of Formula F:

wherein,

W—Y—Z is selected from C(O)OCH₂, OC(O)CH₂, CH₂C(O)O, and CH₂OC(O);

R^(w), R^(x), and R^(y) are each independently selected from a hydrogenatom or a substituted or unsubstituted C₁-C₃alkyl group, or R^(w) andR^(z) are taken together with their adjacent carbon atoms to form adouble bond; and

k is an integer selected from 0, 1 and 2.

According to one aspect, the compound of the invention is a compound ofFormula II, and one of R³ or R⁴ is a group of Formula F. In oneembodiment of this aspect, R^(w) is a methyl group. In anotherembodiment, R^(w) is a methyl group and each of R^(x) and R^(y) arehydrogen atoms. In another embodiment, R^(x) and R^(y) are each a methylgroup and R^(w) is a hydrogen. In yet another embodiment, R^(w) andR^(x) are taken together with their adjacent carbon atoms to form adouble bond. In yet another embodiment, R^(w) and R^(x) are takentogether with their adjacent carbon atoms to form a double bond, andR^(y) is a hydrogen.

According to another aspect, the compound of the invention is a compoundof Formula II, and R³ and R⁴ are each independently a group of FormulaF. In one embodiment of this aspect, R^(w) is a methyl group. In anotherembodiment, R^(w) is a methyl group and each of R^(x) and R^(y) arehydrogen atoms. In another embodiment, R^(x) and R^(y) are each a methylgroup and R^(w) is a hydrogen. In yet another embodiment, R^(w) andR^(x) are taken together with their adjacent carbon atoms to form adouble bond. In yet another embodiment, R^(w) and R^(x) are takentogether with their adjacent carbon atoms to form a double bond, andR^(y) is a hydrogen.

The invention further relates to compounds of Formula II, wherein saidcompound is any one or more of Compounds A71, A72, A73, B76, B77, B78,B79, B80 and B81, or a pharmaceutically acceptable salt or solvatethereof.

B. Oligomers and Gemini Dimers

In further aspects of the invention, the compounds of Formula I maycomprise two or more 1,3PDS molecules linked together. Therefore,another aspect of the invention relates to oligomers of 1,3PDS, i.e., amolecule comprising, or consisting essentially of, or consisting of twoor more molecules of 1,3PDS linked together through cleavablelinkage(s). Thus, the invention relates to a compound of Formula III:

A-(L^(x)-A)_(p)-L^(x)-A  (III)

wherein,

A is 1,3-propanedisulfonic acid moiety;

L^(x) is a cleavable linkage for covalently and dissociably couplingtogether two 1,3PDS moieties respectively; and

p is 0 or an integer selected from 1, 2, 3, 4, or 5;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

Alternatively, the invention relates to a compound of Formula III-A:

L^(y)(A)_(m)  (III-A)

wherein,

m is an integer from 2 to 5;

A is 1,3-propanedisulfonic acid moiety; and

L^(y) is a multivalent carrier moiety for covalently and dissociablycoupling from two to five A moieties, at either sulfonic acid end of A;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

The free sulfonic acid group at each end may or may not be furtheresterified with a R³ or R⁴ group as described herein. Those skilled inthe art will be capable to select proper linkers and linkage site andtest the resulting product for efficacy and for capability of cleavageunder various chemical and/or biological conditions.

The following structures are examples of prodrugs of the inventioncontaining more than one 1,3PDS moiety and are illustrative of theinvention only and they should not be construed as further limiting.

or a pharmaceutically acceptable salt or solvate of any one of CompoundsG1 to G4.

C. Non-Ester Prodrugs

In one aspect, the invention relates to compounds of Formula IV:

wherein,

R¹⁸ is selected from OR³, NH₂, —NHC(O)R⁵, —NHC(NH)NHR⁵,—NH(C₅-C₁₀heteroaryl), —NR²⁰R²¹, R¹⁴, and —NHR¹⁵;

R¹⁹ is selected from NH₂, —NHC(O)R⁵, —NHC(NH)NHR⁵,—NH(C₅-C₁₀heteroaryl), —NR²⁰R²¹, R¹⁴, and —NHR¹⁵;

R³, R⁵, R¹⁴, and R¹⁵ are as previously defined; and

R²⁰ and R²¹ are taken together with their adjacent nitrogen atom to forma mono or bicyclic heteroaryl having from 5 to 10 ring members;

or a pharmaceutically acceptable salt or solvate thereof.

The invention relates to compounds of Formula IV, wherein R¹⁸ is OH, ora pharmaceutically acceptable salt thereof. The invention also relatesto compounds of Formula IV, wherein R¹⁹ is —NHC(O)R⁵. The invention alsorelates to compounds of Formula IV, wherein R¹⁹ is —NHC(NH)NHR⁵. Theinvention also relates to compounds of Formula IV, wherein R¹⁹ is—NH(C₅-C₁₀heteroaryl). For example, R¹⁹ is —NH(C₅-C₁₀heteroaryl),wherein said C₅-C₁₀heteroaryl is selected from thiazol-2-yl,imidazol-2-yl, 1,3-oxazol-2-yl, 1,3-benzothiazol-2-yl,1,3-benzoimidazol-2-yl, and 1,3-benzoxazol-2-yl. In another example, R¹⁹is —NH(C₅-C₁₀heteroaryl), wherein said C₅-C₁₀heteroaryl is selected fromthiazol-2-yl, imidazol-2-yl, and 1,3-oxazol-2-yl. In a further example,R¹⁹ is —NH(thiazol-2-yl), and all other groups are as previouslydefined.

The invention also relates to compounds of Formula IV, wherein said R⁵is selected from hydrogen and a substituted or unsubstituted groupselected from C₁-C₁₂alkyl, C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl,C₆-C₁₅aryl, and C₅-C₁₅heteroaryl. As an example, R⁵ is selected fromhydrogen and a substituted or unsubstituted C₁-C₁₂alkyl. In anotherexample, R⁵ is hydrogen. In a further example, R⁵ is a substituted orunsubstituted C₁-C₆alkyl, and all other groups are previously defined.

The following structures are examples of prodrugs of the inventioncontaining non-sulfonate ester prodrug moiety and are illustrative ofthe invention only and they should not be construed as further limiting:

or a pharmaceutically acceptable salt or solvate of any one of CompoundsN1 to N18.

D. Precursor Prodrugs

In further aspects of the invention, the compounds of the invention areprecursors of 1,3PDS, i.e. Therefore, another aspect of the inventionrelates to a molecule comprising, or consisting essentially of, orconsisting of . . . . Thus, the invention relates to a compound ofFormula V:

wherein,

B and D are each independently a precursor of an SO₃H group;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

The invention further relates to compounds of Formula (V), wherein B andD are each independently selected from SH and SO₂H.

The following structure is an example of a precursor prodrug of theinvention, is illustrative of the invention only and should not beconstrued as further limiting:

or a pharmaceutically acceptable salt or solvate of Compound P1.

III. Synthesis of the Compounds of the Invention

In general, all compounds of the present invention may be prepared bythe methods illustrated in the Examples hereinafter and/or otherconventional methods, using readily available and/or conventionallypreparable starting materials, reagents and conventional synthesisprocedures. In these reactions, it is also possible to make use ofvariants which are in themselves known, but are not mentioned here.Certain novel and exemplary methods of preparing the inventive compoundsare described in the Exemplification section. Such methods are withinthe scope of this invention. Functional and structural equivalents ofthe compounds described herein and which have the same generalproperties, wherein one or more simple variations of substituents aremade which do not adversely affect the essential nature or the utilityof the compound are also included.

More particularly, the sulfonate ester prodrugs of the present inventionmay be prepared by the methods illustrated in the Examples sectionhereinafter.

The compounds of the present invention may be readily prepared inaccordance with the synthesis schemes and protocols described herein, asillustrated in the specific procedures provided. However, those skilledin the art will recognize that other synthetic pathways and/or modifiedsynthetic pathways for preparing the compounds of this invention may beused, and that the following is provided merely by way of example, andis not limiting to the present invention. See, e.g., “ComprehensiveOrganic Transformations” by R. Larock, VCH Publishers (1989),incorporated herein by reference. It will be further recognized thatvarious protecting and deprotecting strategies will be employed that arestandard in the art (See, e.g., “Protective Groups in Organic Synthesis”by Greene and Wuts (1991), incorporated herein by reference). Thoseskilled in the relevant arts will recognize that the selection of anyparticular protecting group (e.g., amine, hydroxyl, thio, and carboxylprotecting groups) will depend on the stability of the protected moietywith regards to the subsequent reaction conditions and will understandthe appropriate selections.

Further illustrating the knowledge of those skilled in the art is thefollowing sampling of the extensive chemical literature: “Chemistry ofthe Amino Acids” by J. P. Greenstein and M. Winitz, John Wiley & Sons,Inc., New York (1961); “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” by J. March, 4th Edition, John Wiley & sons(1992); T. D. Ocain, et al., J. Med. Chem., 31, 2193-99 (1988); E. M.Gordon, et al., J. Med. Chem., 31, 2199-10 (1988); “Practice of PeptideSynthesis” by M. Bodansky and A. Bodanszky, Springer-Verlag, New York(1984); “Asymmetric Synthesis: Construction of Chiral Molecules UsingAmino Acids” by G. M. Coppola and H. F. Schuster, John Wiley & Sons,Inc., New York (1987); “The Chemical Synthesis of Peptides” by J. Jones,Oxford University Press, New York (1991); and “Introduction of PeptideChemistry” by P. D. Bailey, John Wiley & Sons, Inc., New York (1992),each incorporated herein by reference.

The synthesis of compounds of the invention is preferably carried out ina solvent. Suitable solvents are liquids at ambient room temperature andpressure or remain in the liquid state under the temperature andpressure conditions used in the reaction. The choice of solvent iswithin the general skills of the skilled artisan and will depend on thereaction conditions, such, temperature, the nature of the reagents andstarting material, solubility and stability of the reagents and startingmaterial, the type of reaction, and the like. Depending on thecircumstances, solvents may be distilled or degassed. Solvents may be,for example, aliphatic hydrocarbons (e.g., hexanes, heptanes, ligroin,petroleum ether, cyclohexane, or methylcyclohexane) and halogenatedhydrocarbons (e.g., methylenechloride, chloroform, carbontetrachloride,dichloroethane, chlorobenzene, or dichlororbenzene); aromatichydrocarbons (e.g., benzene, toluene, tetrahydronaphthalene,ethylbenzene, or xylene); ethers (e.g., diglyme, methyl-tert-butylether, methyl-tert-amyl ether, ethyl-tert-butyl ether, diethylether,diisopropylether, tetrahydrofuran or methyltetrahydrofurans, dioxane,dimethoxyethane, or diethyleneglycol dimethylether); amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide); nitriles (e.g.,acetonitrile); ketones (e.g., acetone); esters (e.g., methyl acetate orethyl acetate); alcohols (e.g., methanol, ethanol, isopropanol); waterand mixtures thereof.

“Activated esters” and equivalent expressions may be represented by theformula COX for carboxylate esters or SO₂X for sulfonate esters, where Xis a leaving group, typical examples of which include halogens (e.g.chloride or bromide), N-hydroxysulfosuccinimidyl andN-hydroxysuccinimidyl groups; aryloxy groups substituted withelectron-withdrawing groups (e.g., p-nitro, pentafluoro, pentachloro,p-cyano, or p-trifluoromethyl); and carboxylic acids activated by acarbodiimide or other conventional coupling reagents to form ananhydride or mixed anhydride, e.g., —OCOR^(a) or —OCNR^(a)NHR^(b), whereR^(a) and R^(b) are independently C₁-C₆ alkyl, C₅-C₈ alkyl (e.g.,cyclohexyl), C₁-C₆ perfluoroalkyl, or C₁-C₆ alkoxy groups. An activatedester may be formed in situ or may be an isolable reagent. The esterleaving group may be, for example, sulfosuccinimidyl esters,pentafluorothiophenol esters, sulfotetrafluorophenol, substituted orunsubstituted C₁-C₆ alkyl (such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), orsubstituted or unsubstituted C₆-C₁₄ aryl or heterocyclic groups, such as2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-dibromoethyl,2,2,2-trichloroethyl, 3-fluoropropyl, 4-chlorobutyl, methoxymethyl,1,1-dimethyl-1-methoxymethyl, ethoxymethyl, N-propoxymethyl,isopropoxymethyl, N-butoxymethyl, tert-butoxymethyl, 1-ethoxyethyl,1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl,3-methoxypropyl-4-methoxybutyl, fluoromethoxymethyl,2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl,3-fluoropropoxymethyl, 4-chlorobutoxyethyl, di bromomethoxyethyl,2-chloroethoxypropyl, fluoromethoxybutyl, 2-methoxyethoxymethyl,ethoxymethoxyethyl, methoxyethoxypropyl, methoxyethoxybutyl, benzyl,phenethyl, 3-phenylpropyl, 4-phenylbutyl, α-naphthylmethyl,β-naphthylmethyl, diphenylmethyl, triphenylmethyl,α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl,2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 2-nitrobenzyl,4-nitrobenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl,4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl,4-cyanobenzyldiphenylmethyl, or bis(2-nitrophenyl)methyl groups.

IV. Pharmaceutical Compositions

Preferably, the compounds of the invention are formulated prior toadministration into pharmaceutical compositions using techniques andprocedures well known in the art. Accordingly, in another embodiment,the present invention relates to pharmaceutical compositions (e.g. solidor semi-solid mixtures, solutions, suspensions or emulsions) comprisingeffective amounts of one or more compounds according to any of theFormulae herein and a pharmaceutically acceptable vehicle, as well asmethods of using and manufacturing such pharmaceutical compositions.

The pharmaceutical compositions are formulated for suitableadministration (orally, parenterally, (IV, IM, depo-IM, SC, anddepo-SC), sublingually, intranasally (inhalation), intrathecally,topically, or rectally). Suitable pharmaceutical vehicles include,without limitation, any non-immunogenic pharmaceutical carrier ordiluent suitable for oral, parenteral, nasal, mucosal, transdermal,topical, intrathecal, rectal, intravascular (IV), intraarterial (IA),intramuscular (IM), and subcutaneous (SC) administration routes, such asphosphate buffer saline (PBS). Also, the present invention includes suchcompounds which have been lyophilized and which may be reconstituted toform pharmaceutically acceptable formulations for administration, as byintravenous, intramuscular, or subcutaneous injection. Administrationmay also be intradermal or transdermal.

Preferably, the pharmaceutical composition of the invention is suitablefor oral administration. The formulations may conveniently be presentedin unit dosage form and may be prepared by any methods well known in theart of pharmacy. In general, the formulations are prepared by uniformlyand intimately bringing into association a compound of the presentinvention with a pharmaceutically acceptable vehicle (e.g. an inertdiluent or an assimilable edible, liquid or finely divided solid (orboth), carrier) and, optionally, one or more accessory ingredients andthen, if necessary, shaping the product. The amount of the therapeuticagent in such therapeutically useful compositions is such that asuitable dosage will be obtained.

Formulations of the invention suitable for oral administration may be inthe form of capsules (e.g. hard or soft shell gelatin capsule), cachets,pills, tablets, lozenges, powders, granules, pellets, dragees, e.g.,coated (e.g., enteric coated) or uncoated, or as a solution or asuspension in an aqueous or non-aqueous liquid, or as an oil-in-water orwater-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles(using an inert base, such as gelatin and glycerin, or sucrose andacacia), and the like, each containing a predetermined amount of acompound of the present invention as an active ingredient. A compound ofthe present invention may also be administered as a bolus, electuary orpaste, or incorporated directly into the subject's diet. Moreover, thecompounds can be orally formulated to (a) provide for instant or rapiddrug release (i.e., have no coating on them); (b) be coated, e.g., toprovide for sustained drug release over time; or (c) be entericallycoated for better gastrointestinal tolerability or protection fromdegradation in the stomach.

In solid dosage forms of the invention for oral administration theactive ingredient is typically mixed with one or more pharmaceuticallyacceptable carriers or non-active pharmaceutical ingredients, such assodium citrate or dicalcium phosphate, or any of the following: fillersor extenders (e.g. starches, lactose, sucrose, glucose, mannitol, orsilicic acid); binders (e.g. carboxymethylcellulose, alginates, gelatin,polyvinyl pyrrolidone, sucrose or acacia); humectants (e.g. glycerol);disintegrating agents (e.g. agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate);solution retarding agents (e.g., as paraffin); absorption accelerators(e.g. quaternary ammonium compounds); wetting agents (e.g., cetylalcohol and glycerol monostearate); absorbents (e.g., kaolin andbentonite clay); lubricants (e.g. talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof); and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

Peroral compositions typically also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically acceptable vehiclessuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, tragacanth, and sodium alginate; typical wetting agentsinclude lecithin and polysorbate 80; and typical preservatives includemethyl paraben and sodium benzoate. Peroral liquid compositions may alsocontain one or more components such as sweeteners, flavoring agents andcolorants.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions, and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. In all cases, the composition must be sterileand must be fluid to the extent that easy syringability exists. It mustbe stable under the conditions of manufacture and storage and must bepreserved against the contaminating action of microorganisms such asbacteria and fungi. Sterile injectable solutions can be prepared byincorporating the therapeutic agent in the required amount in anappropriate solvent with one or a combination of ingredients enumeratedabove, as required, followed by filtered sterilization. Generally,dispersions are prepared by incorporating the therapeutic agent into asterile vehicle which contains a basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, themethods of preparation are vacuum drying and freeze-drying which yieldsa powder of the active ingredient (i.e., the therapeutic agent) plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof. Solvent or dispersion medium suitable for injectableuse are, for example, water, ethanol, polyols (for example, glycerol,propylene glycol, and liquid polyethylene glycol, and the like),suitable mixtures thereof, and vegetable oils. Proper fluidity ismaintained, for example, by the maintenance of the required particlesize in the case of dispersion and by the use of surfactants. Preventionof the action of microorganisms can be achieved by various antibacterialand antifungal agents, for example, parabens, chlorobutanol, phenol,ascorbic acid, thimerosal, and the like. In many cases, isotonic agentsare included, for example, sugars, sodium chloride, or polyalcohols suchas mannitol and sorbitol, in the composition. Prolonged absorption ofthe injectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate or gelatin.

Pharmaceutical formulations are also provided which are suitable foradministration as an aerosol, by inhalation. These formulations comprisea solution or suspension of the desired compound of any Formula hereinor a plurality of solid particles of such compound(s). As a liquid, theformulation will comprise, for example, a water-soluble compound of theinvention, or a salt thereof, in a carrier which comprises water. Asurfactant may be present which lowers the surface tension of theformulation sufficiently to result in the formation of droplets withinthe desired size range when subjected to nebulization. On the otherhand, solid particles can be obtained by processing the solid form of acompound, or a salt thereof, in any appropriate manner known in the art,such as by micronization. The liquid droplets or solid particles shouldhave a particle size in the range of about 0.5 to about 5 microns. Thesize of the solid particles or droplets will be, for example, from about1 to about 2 microns. The desired formulation may be placed in a smallchamber and nebulized. Nebulization may be accomplished by compressedair or by ultrasonic energy to form a plurality of liquid droplets orsolid particles comprising the agents or salts. In this respect,commercial nebulizers are available to achieve this purpose.

The compositions of this invention can also be administered topically toa subject, e.g., by the direct lying on or spreading of the compositionon the epidermal or epithelial tissue of the subject, or transdermallyvia a “patch”. Such compositions include, for example, lotions, creams,solutions, gels and solids. These topical compositions may comprise aneffective amount, usually at least about 0.1%, or even from about 1% toabout 5%, of an agent of the invention. Suitable carriers for topicaladministration typically remain in place on the skin as a continuousfilm, and resist being removed by perspiration or immersion in water.Generally, the carrier is organic in nature and capable of havingdispersed or dissolved therein the therapeutic agent. The carrier mayinclude pharmaceutically acceptable emollients, emulsifiers, thickeningagents, solvents and the like.

Other compositions useful for attaining systemic delivery of the subjectagents include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.The compound(s) of the invention may also be administered parenterally,intraperitoneally, intraspinally, or intracerebrally. For suchcompositions, the compound(s) of the invention can be prepared inglycerol, liquid polyethylene glycols, and mixtures thereof and in oils.Under ordinary conditions of storage and use, these preparations maycontain a preservative to prevent the growth of microorganisms.

To administer the compound(s) of the invention by other than parenteraladministration, it may be useful to coat the compound(s) with, orco-administer the compound(s) with a material to prevent itsinactivation. For example, the compound(s) of the invention may beadministered to a subject in an appropriate carrier, for example,liposomes, or a diluent. Pharmaceutically acceptable diluents includesaline and aqueous buffer solutions. Liposomes includewater-in-oil-in-water CGF emulsions as well as conventional liposomes.

Pharmaceutical compositions according to the invention may also becoated by conventional methods, typically with pH or time-dependentcoatings, such that the compound(s) of the invention is released in thevicinity of the desired location, or at various times to extend thedesired action. Such dosage forms typically include, but are not limitedto, one or more of cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose,waxes, and shellac.

Dosage forms provide the compound in a pharmaceutical composition of theinvention for in vivo administration to a subject, e.g. a human patient.It is understood that appropriate doses depend upon a number of factorswithin the knowledge of the ordinarily skilled physician, veterinarian,or researcher (e.g. see Wells et al. eds., Pharmacotherapy Handbook,2^(nd) Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), incorporated herein byreference). The dose(s) of the compound(s) of the invention will vary,for example, depending upon a variety of factors including, but notlimited to: the activity, biological and pharmacokinetic propertiesand/or side effects of the compound being used; the age, body weight,general health, gender, and diet of the subject; the time ofadministration, the route of administration, the rate of excretion, andany drug combination, if applicable; the effect which the practitionerdesires the compound to have upon the subject; and the properties of thecompound being administered (e.g. bioavailability, stability, potency,toxicity, etc). Such appropriate doses may be determined using theassays described herein or known in the art. When one or more of thecompounds of the invention is to be administered to humans, a physicianmay for example, prescribe a relatively low dose at first, subsequentlyincreasing the dose until an appropriate response is obtained.

There are no particular limitations on the dose of each of the compoundsfor use in the composition of the present invention. Exemplary dosesinclude milligram or microgram amounts of the compound per kilogram ofsubject or sample weight (e.g., about 50 micrograms per kilogram toabout 500 milligrams per kilogram, about 1 milligram per kilogram toabout 100 milligrams per kilogram, about 1 milligram per kilogram toabout 50 milligram per kilogram, about 1 milligram per kilogram to about10 milligrams per kilogram, or about 3 milligrams per kilogram to about5 milligrams per kilogram). Additional exemplary doses include single ormultiple doses of about 5 to about 1000 mg, about 25 to about 800 mg,about 25 to about 400 mg, about 50 to about 200 mg, or about 50, about100, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400mg, or about 500 mg, and, preferably, daily or twice daily, or lower orhigher amounts. Further exemplary doses include daily doses in a humanof about 50 mg to about 4000 mg, about 100 mg to about 3500 mg, about100 mg to about 2500 mg, about 100 mg to about 1200 mg, about 100 mg toabout 800 mg, about 400 mg to about 2500 mg, about 400 mg to about 1200mg, about 400 mg to about 800 mg, about 800 mg to about 4000 mg, about800 mg to about 3500 mg, about 800 mg to about 2500 mg, about 800 mg toabout 1200 mg, about 1200 mg to about 4000 mg, about 1200 mg to about3200 mg, about 1200 mg to about 2500 mg, administered as a single dailydose or divided in multiple doses throughout the day. Examples ofdosages of 1,3PDS (e.g. herein using molar equivalence or less of theprodrug) are described in PCT published applications WO 2007/004072, WO2007/125385 and WO 2008/078176, incorporated herein by reference intheir entirety for all purposes.

It is generally advantageous to formulate parenteral compositions indosage unit form for ease of administration and uniformity of dosage.The term “unit dosage form” refers to a physically discrete unitsuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical vehicle. The specification for the dosage unitforms of the invention may vary and are dictated by and directlydependent on (a) the unique characteristics of the therapeutic agent andthe particular therapeutic effect to be achieved, and (b) thelimitations inherent in the art of compounding such a therapeutic agentfor the prevention of treatment of the disease or disorder.

Administration of the compounds and compositions of the presentinvention to a subject to be treated can be carried out using knownprocedures, at dosages and for periods of time effective to achieved thedesired purpose. Dosage regimens can be adjusted to provide the optimumtherapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. Preferably,the compound(s) of the invention is administered at a therapeuticallyeffective dosage sufficient to reduce the disease's or disorder'ssymptoms in a subject, preferably a human subject.

The compound(s) of the invention may be packaged as part of a kit or apharmaceutical package, optionally including a container (e.g.packaging, a box, a vial, etc). The kit may be commercially usedaccording to the methods described herein and may include instructionsfor use in a method of the invention. Additional kit components mayinclude acids, bases, buffering agents, inorganic salts, solvents,antioxidants, preservatives, or metal chelators. The additional kitcomponents are present as pure compositions, or as aqueous or organicsolutions that incorporate one or more additional kit components. Any orall of the kit components optionally further comprise buffers.

V. Methods of Uses of the Compounds

Another aspect of the invention pertains to a method for treating adisease or disorder in a subject by administering an effective amount ofa prodrug of the present invention. The term “subject” includes livingorganisms with a disease or disorder treatable by 1,3PDS, or which aresusceptible to such a disease or disorder, e.g. amyloid A amyloidosis,renal disorders, diabetic nephropathy, hyperglycemia, dyslipidemia,diabetes mellitus (e.g. type 1 or type 2), diabetes with features ofmetabolic syndrome, metabolic syndrome, any underlying or resultingdisease or symptom of any the foregoing, or any combination thereof.Examples of subjects include humans, monkeys, cows, rabbits, sheep,goats, pigs, dogs, cats, rats, mice, and transgenic species thereof. Theterm “subject” preferably includes animals susceptible to statescharacterized by amyloidosis and/or metabolic diseases, e.g. mammals,e.g. primates, e.g. humans. The animal can also be an animal model for adisorder, e.g., an AA amyloidosis mouse model, or an obese or diabeticmouse or rat model.

In certain embodiments of the invention, the human subject is in need oftreatment by the methods of the invention, and is selected for treatmentbased on this need. A subject in need of treatment is art-recognized,and includes subjects that have been identified as having any of theforegoing disease or disorder, has a symptom of such a disease ordisorder, or is at risk of such a disease or disorder, and would beexpected, based on diagnosis, e.g., medical diagnosis, to benefit fromtreatment (e.g., curing, healing, preventing, alleviating, relieving,altering, remedying, ameliorating, improving, or affecting the diseaseor disorder, the symptom of the disease or disorder, or the risk of thedisease or disorder).

For example, the human subject may be a human over 20 year sold, over 30years old, human over 40 years old, a human over 50 years old, a humanover 60 years old, a human over 70 years old, a human over 80 years old.The subject may be a female human, including a postmenopausal femalehuman, who may be on hormone (estrogen) replacement therapy. The subjectmay also be a male human. In another embodiment, the subject is under 40years old.

In one aspect, the subject has a disease that provokes a sustained acutephase response. For example, such diseases include chronic inflammatorydisorders (e.g. long standing inflammation), chronic local or systemicmicrobial infections, and malignant neoplasms. For example, such adisease includes Rheumatoid Arthritis or Familial Mediterranean Fever (agenetic disease).

In another aspect, the subject has amyloid A amyloidosis, with orwithout renal impairment. For example, the subject has amyloid Aamyloidosis with renal, which may vary from mild, moderate and severeimpairement.

In another aspect, the subject's rate of creatinine clearance is lowerthan about 80 mL/min, lower than about 30 mL/min (severe), from about 30to about 80 mL/min (moderate), or greater than about 80 mL/min (mild tonone).

In some aspects, the subject may have symptoms of a metabolic disease orcondition, such as diabetes (e.g. type II diabetes), metabolic syndrome,obesity, etc. In another embodiment, the subject may have symptoms oftype II diabetes and be overweight. For example, the subject has a bodymass index (BMI) of 25 or more, a BMI between 25 and 30, or a BMI of 30or more. The Body Mass Index, or BMI is a measure of a person's weighttaking into account their height. It is given by the formula: BMI equalsa person's weight (mass) in kilograms divided by the square of theperson's height in metres. In some aspects, the subject is diabetic andrequires administration of exogenous insulin. In one aspect, the subjectis diabetic and does not require exogenous insulin, and the treatmentwith the compound of the invention allows delaying the requirement fortreating the diabetic patient with insulin.

“Preventing” or “prevention” is intended to refer at least the reductionof likelihood or the risk of (or susceptibility to) acquiring a diseaseor disorder (i.e., causing at least one of the clinical symptoms of thedisease not to develop in a patient that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease). The term “prevention” or “preventing” is alsoused to describe the administration of a compound or composition of theinvention to a subject who is at risk of (or susceptible to) such adisease or condition. Patients amenable to treatment for prevention ofthe disease or condition include individuals at risk of the disease orcondition but not showing symptoms, as well as patients presentlyshowing symptoms. Predisposing factors identified or proposed in thescientific literature include, among others, genetic factors,environmental factors, chronic inflammation and other conditions (suchas ones predisposing to AA amyloidosis), sedentary lifestyle, eatinghabits, and metabolic disorders predisposing a subject to a disease ordisorder as described herein. Prevention also includes delaying onset ofcertain endpoint, for example, delaying the need for dialysis in renallyimpaired patients, or the need for insulin in diabetes patients.

“Treating” or “treatment” of any disease or disorder refers, in someembodiments, to ameliorating at least one disease or disorder (i.e.,arresting or reducing the development of the disease or at least one ofthe clinical symptoms thereof). In certain embodiments “treating” or“treatment” refers to ameliorating at least one physical parameter. Incertain embodiments, “treating” or “treatment” refers to inhibiting thedisease or disorder, either physically, (e.g., stabilization of adiscernible symptom), physiologically, (e.g., stabilization of aphysical parameter), or both. In certain embodiments, “treating” or“treatment” refers to delaying the onset of the disease or disorder. Theterm “treating” refers to any indicia of success in the treatment oramelioration of an injury, pathology or condition, including anyobjective or subjective parameter such as abatement; remission;diminishing of symptoms or making the injury, pathology or conditionmore tolerable to the subject; improving a subject's physical or mentalwell-being, reducing symptoms experienced by the patient; and, in somesituations additionally improving at least one parameter of a renaldisorder (creatinine clearance, proteinuria, etc) or metabolic disorder(e.g. glucose tolerance, insulin secretion, reducing serum triglycerideslevels, etc). The treatment or amelioration of symptoms can be based onobjective or subjective parameters; including the results of a physicalexamination or the subject's evaluation of symptoms, or of a test knownin the art (e.g. glucose level, etc). The treatment or amelioration ofsymptoms also includes delaying the onset of dialysis, i.e. thenecessity for dialysis.

As used herein the term “therapeutically effective amount” refers to theamount or dose of the compound, upon single or multiple doseadministration to the patient, which provides the desired effect in thepatient under diagnosis or treatment. An effective amount can be readilydetermined by the attending diagnostician, as one skilled in the art, bythe use of known techniques and by observing results obtained underanalogous circumstances. In determining the effective amount or dose ofcompound administered, a number of factors are considered by theattending diagnostician, including, but not limited to: the size, age,and general health of the subject; the specific disease(s) involved; thedegree of or involvement or the severity of the disease; the response ofthe individual subject; the particular compound administered; the modeof administration; the bioavailability characteristics of thepreparation administered; the dose regimen selected; the use ofconcomitant medication; and other relevant circumstances.

Improvement in condition is present within the context of the presentinvention if there is a measurable difference between the performancesof subjects treated using the methods of the invention as compared tomembers of a placebo group, historical control, or between subsequenttests given to the same subject.

It is to be understood that wherever values and ranges are providedherein, e.g., in ages of subject populations, dosages, and blood levels,all values and ranges encompassed by these values and ranges, are meantto be encompassed within the scope of the present invention. Moreover,all values in these values and ranges may also be the upper or lowerlimits of a range.

In certain embodiments, the compounds and composition according to theinvention can be used in combination therapy with at least one othertherapeutic or a nutraceutical agent. The compounds of the inventionwhen administered in association with at least one other agent(s), canact additively or, in certain embodiments, synergistically.

The compounds of the invention can be administered prior, subsequent toor concomitantly with the other agent. The compositions of the presentinvention can be administered with the other therapeutic agent as partof the same pharmaceutical composition as, or in a different compositionfrom, that containing the compounds of the present invention. The atleast one other agent can be effective for treating the same ordifferent disease, disorder, or condition. Preferably, the other agentis suitable for the treatment of symptoms of a metabolic disorder, e.g.diabetes, diabetes with features of metabolic syndrome, metabolicsyndrome, and the like.

Methods of the present invention include administration of one or morecompounds or pharmaceutical compositions of the present invention andone or more other therapeutic agents provided that the combinedadministration does not inhibit the therapeutic efficacy of the one ormore compounds of the present invention and/or does not produce adversecombination effects.

In some aspects, the combination therapy comprises alternating betweenadministering a composition of the present invention and a compositioncomprising another therapeutic agent, e.g., to minimize adverse sideeffects associated with a particular drug. When a compound of thepresent invention is administered concurrently with another therapeuticagent that potentially can produce adverse side effects including, butnot limited to, toxicity, the therapeutic agent can advantageously beadministered at a dose that falls below the threshold at which theadverse side effect is elicited. A pharmaceutical composition can alsofurther comprise substances to enhance, modulate and/or control release,bioavailability, therapeutic efficacy, therapeutic potency, stability,and the like.

The compounds or pharmaceutical compositions of the present inventioninclude, or can be administered to a patient together with, anothertherapeutic drug that may be available over-the-counter or byprescription. Therapeutic drugs as well as nutraceuticals useful in acombination with a therapeutic compound of the present invention areknown to the skilled artisan. Preferred therapeutic drugs to be usedwith the compounds or pharmaceutical compositions of the presentinvention are therapeutic drugs useful in the prevention or treatmentof, but not limited to, chronic inflammation, nephropathy, or diabetesand other metabolism disorders, or any disease, disorder or symptomassociated with any of the conditions disclosed herein.

Preferred therapeutic drugs to be used with the 1,3PDS prodrugs anddimers and oligomers of the present invention are therapeutic drugsuseful in the prevention or treatment of renal disorders as well asdiabetes and associated symptoms and syndromes. PCT patent applicationWO 2008/078176 (incorporated herein by reference) provide a long butnon-exhaustive list of “therapeutic drugs” that can be useful, incombination, according to the invention.

VI. Standard Methods for Testing the Compounds of the Invention

The compounds according to the invention can be further analyzed, testedor validated using a variety of in vitro assays, or in vivo assays toconfirm their safety and bioavailabity, their capability to deliver1,3PDS, etc. The following are illustrative of the type of biologicalassays that can be conducted to assess the instant compounds.

i) Determination of Enzymatic Cleavage of Prodrugs In Vitro

For orally administered prodrugs, it is generally desirable that theprodrug remains mostly intact (i.e., uncleaved or not converted to theparent drug) while in the gastrointestinal tract and be cleaved (i.e.,to release the parent drug) while in the systemic circulation. A usefullevel of stability can at least in part be determined by the mechanismand kinetics of absorption of the prodrug by the gastrointestinal tract.A useful level of lability can at least in part be determined by thepharmacokinetics of the prodrug and parent drug in the systemiccirculation. In general, prodrugs that are more stable in a Caco-2 S9and/or pancreatin assay and are more labile in rat plasma, human plasma,rat liver S9, and/or human liver S9 preparation can be useful as anorally administered prodrug. The results of tests, for determining theenzymatic cleavage of prodrugs in vitro can be used to select prodrugsfor in vivo testing.

ii) Bioavailability of Prodrugs In Vivo

Prodrugs that provide, following administered to a patient or a subject,a certain level of bioavailability of the corresponding parent drug canbe useful as therapeutic agents. Bioavailability of the compounds of theinvention and of released 1,3PDS can be measured in vivo (humans and/orlaboratory animals) using methods well known in the art.

iii) Toxicity

A variety of different parameters can be monitored to assess toxicity.Examples of such parameters include, but are not limited to, cellproliferation, monitoring activation of cellular pathways fortoxicological responses by gene or protein expression analysis, DNAfragmentation, changes in the composition of cellular membranes,membrane permeability, activation of components of death-receptors ordownstream signaling pathways (e.g., caspases), generic stressresponses, NF-kappaB activation and responses to mitogens. Relatedassays are used to assay for apoptosis (a programmed process of celldeath) and necrosis, including cGMP formation and NO formation.

Toxicity and therapeutic efficacy of the compound(s) and composition(s)of the invention can be determined by standard pharmaceutical proceduresin cell cultures or experimental animals, e.g., for determining the LD50(the dose lethal to 50% of the population) and the ED50 (the dosetherapeutically effective in 50% of the population). The dose ratiobetween toxic and therapeutic effects is the therapeutic index and canbe expressed as the ratio LD50/ED50, and usually a larger therapeuticindex is more efficacious. While agents that exhibit toxic side effectsmay be used, care should be taken to design a delivery system thattargets such agents to the site of affected tissue in order to minimizepotential damage to unaffected cells and, thereby, reduce side effects.

iv) Gastrointestinal Absorption

The compounds or drugs according to the invention can be furtheranalyzed, tested or validated for their ability to be absorbed by thegut and/or intestine if so desired.

Intestinal permeability and transport of a drug candidate may beestimated using a variety of in vitro, in situ, as well as in vivomodels (Balimane et al. (2000) J Pharmacol Toxicol Methods 44:385-401;Hidalgo I. (2001) Curr Top Med Chem 1:385-401, Hillgreen K, Kato A andBorchardt R. (1995) 15:83-109, each incorporated herein by reference).

For instance, parallel artificial membrane permeability (PAMPA) assayand cell-based systems such as Caco-2 and Mardin-Darby canine kidney(MDCK) cells are the most frequently used in vitro models. The PAMPAmodel consists of a hydrophobic filter material coated with a mixture oflecithin/phospholipids dissolved in an inert organic solvent creating anartificial lipid membrane barrier that mimics the intestinal epithelium.Caco-2 cells, a human colon adenocarcinoma, undergo spontaneousenterocytic differentiation in culture and become polarized cells withwell-established tight junctions, resembling intestinal epithelium inhumans. Caco-2 cell model has been the most popular and the mostextensively characterized cell-based model in examining the permeabilityof drugs in both the pharmaceutical industries and academia.Alternatively, MDCK cells which also develop tight junctions and formmonolayers of polarized cells are used.

An in situ study such as an intestinal perfusion could also be performedto assess drug absorption. Isolated intestinal segments comprise theabsorptive cells and the underlying muscle layers. As it is commonlyused, this technique only allows sampling from the mucosal side; drugdisappearance is assumed to be equal to drug absorption. Typically, awhole animal absorption study (pharmacokinetic study) will be performedin parallel with the in vitro and/or in situ studies to assessintestinal permeability. In general, drug absorption in animals isbelieved to be a good predictor of absorption in humans.

v) Gastrointestinal Toxicity

The compounds or drugs according to the invention can be furtheranalyzed, tested or validated for gastrointestinal (GI) toxicity.Gastrointestinal toxicity of a compound in vivo can be reliablyestablished through the implementation of a standard battery of generaltoxicological assessments. Generally, regulatory test guidelines fromthe EU, OECD, ICH, FDA and JMOHW are used as reference material for thepreparation of study protocols for such assessments. In North America,the toxicological assessments will generally be carried out incompliance with the United States Food and Drug Administration Title 21Code of Federal Regulations Part 58, Good Laboratory Practice forNon-clinical studies issued on Dec. 22, 1978, Federal Register plussubsequent amendments.

Within the context of such a non-clinical assessment of the toxicity ofa particular compound, GI toxicity may specifically be assessed throughthe monitoring of body weight gain, the gross examination of materialsemitted by the test subject (specifically vomitus and feces) and themonitoring of food/water consumption (appetence). Furthermore, upontermination of a non-clinical toxicological assessment, the retentionand processing of GI tract tissues from the test subject(s) to the slidestage, followed by histopathological examination of said tissues by atrained pathologist, is a useful tool, complementary to theaforementioned “in-life” observations.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents are considered to be within the scope of this inventionand covered by the claims appended hereto. The contents of allreferences, issued patents, and published patent applications citedthroughout this application are hereby incorporated by reference. Theinvention is further illustrated by the following examples, which shouldnot be construed as further limiting.

EXAMPLES

The Examples set forth herein below provide exemplary syntheses ofcertain representative compounds of the invention.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, concentrations, properties,stabilities, and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about.” Atthe very least, each numerical parameter should at least be construed inlight of the number of reported significant digits and by applyingordinary rounding techniques. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the presentspecification and attached claims are approximations that may varydepending upon the properties sought to be obtained. Notwithstandingthat the numerical ranges and parameters setting forth the broad scopeof the embodiments are approximations, the numerical values set forth inthe specific examples are reported as precisely as possible. Anynumerical value, however, inherently contain certain errors resultingfrom variations in experiments, testing measurements, statisticalanalyses and such.

The present invention also relates to novel compounds and the synthesisthereof. The following detailed examples describe how to prepare thevarious compounds and/or perform the various processes of the inventionand are to be construed as merely illustrative, and not limitations ofthe preceding disclosure in any way whatsoever. Those skilled in the artwill promptly recognize appropriate variations from the procedures bothas to reactants and as to reaction conditions and techniques. In somecases, the compounds may be commercially available. Accordingly, thefollowing examples are presented to illustrate how some sulfonate esterprodrugs according to the invention may be prepared.

Commercial material is generally available from known sources, forexample, Sigma-Aldrich, Bachem, Lancaster, Alfa Aesar, etc.

Example 1 General Synthetic Protocol for the Synthesis of Mono andDisulfonate Esters

a) 1,3-Propanedisulfonyl Dichloride:

1,3-Propanedisulfonic acid disodium salt (1,3PDS(2Na)), 74 g, 0.29 mol)was well grounded and dried at 110° C. for 15 h. PCl₅ (72 g, 0.62 mol)was added and the two solids were stirred until they melt. The reactionmixture was stirred for 2 h then cooled to room temperature. Theresulting material was added with caution to ice (200 g), followed byaddition of ethyl acetate (200 mL). The mixture was stirred until aclear two phases was obtained. The organic layer was separated, washedwith hydrochloric acid (1 M), and concentrated under reduced pressure toproduce an amorphous brownish solid. Recrystallization in ether allowedthe isolation of 1,3-propanedisulfonyl dichloride (62 g) as a whitesolid: ¹H NMR (CDCl₃, 500 MHz) δ in ppm 2.78 (q, J=7.0 Hz, 2H), 3.95 (t,J=7.0 Hz, 4H).

Alternate Protocol:

Step 1:

To a solution of 1,3-propanedisulfonic acid disodium salt (23.5 g, 94.7mmol) in water (30 mL) was added a hot solution of BaCl₂.H₂O in H₂O (20mL). A white precipitate was formed. The suspension was heated at ˜80°C. for 2 h then cooled to room temperature and allowed to settle bystanding. The white solid was collected by filtration and dried underhigh vacuum at 120° C. for 15 h to afford barium 1,3-propanedisulfonate(20 g, 62%): ¹H NMR (CDCl₃, 500 MHz) δ 2.04 (m, 2H), 2.92 (t, J=7.0 Hz,4H).

Step 2:

The fine powder of barium 1,3-propanedisulfonate (15 g, 44.17 mmol) wasmixed with phosphorus pentachloride (PCl₅) and heated at 110° C. for 5h. (the mixture melted completely after 1-h heating). The reactionmixture was cooled to room temperature, and then quenched with ice/water(150 mL) and ethyl acetate. The organic layer was isolated, washed withwater, dried over sodium sulfate, and concentrated to dryness, affording1,3-propanedisulfonyl dichloride (6 g): NMR (CDCl₃, 500 MHz) δ 2.78 (q,J=7.0 Hz, 2H), 3.95 (t, J=7.0 Hz, 4H).

b) 3-Phenoxysulfonyl-1-Propanesulfonyl Chloride:

To a cold (0° C.) solution of 1,3-propanedisulfonyl dichloride from Step(a) (4.8 g, 20 mmol) in dichloromethane (30 mL) was added dropwise asolution of phenol (1.88 g, 20 mmol) in dichloromethane/pyridine (20mL:5 mL). The reaction mixture was stirred for 3 h while it wasgradually warmed to room temperature. Aqueous HCl (1M) was added to thereaction mixture. The organic layer was separated, dried over magnesiumsulfate, filtered and concentrated. The residual material was purifiedby silica gel chromatography using hexanes/ethyl acetate (70:30) aseluent to isolate 3-phenoxysylfonyl-1-propanesulfonyl chloride (7.2 g):¹H NMR (500 MHz, CDCl₃) δ in ppm 2.71 (quint, J=7.0 Hz, 2H), 3.52 (t,J=7.0 Hz, 2H), 3.95 (t, J=7.0 Hz, 2H), 7.26-7.45 (m, 5H).

c) 1,3-Propanedisulfonic Acid Monoesters:

(R is R⁴ as previously described)

Step 1: Esterification:

To a cold (0° C.) solution of 3-phenoxysylfonyl-1-propanesulfonylchloride from Step (b) (5.97 g, 20 mmol, see (b)) in CH₂Cl₂ (30 mL) isadded dropwise a solution of the corresponding alcohol (22 mmol) inCH₂Cl₂/pyridine (20 mL/5 mL). The reaction mixture is stirred for 3-15 hwhile it is gradually warmed to room temperature. Aqueous hydrochloricacid (1M) is added to the reaction mixture. The organic layer isseparated, dried over magnesium sulfate and concentrated. The residualmaterial is purified by silica gel chromatography using hexanes/ethylacetate as eluent to isolate the corresponding intermediate1,3-propanesulfonic acid alkyl phenyl ester.

Step 2: Deprotection:

To a solution of the intermediate 1,3-propanesulfonic acid alkyl phenylester from Step 1 (2 mmol) in MeOH (50 mL) is added acetic acid (5 mL)followed by addition of Pd(OH)₂ (200 mg) in water (5 mL). The reactionmixture is stirred under hydrogen (1 atm., balloon) for 2-3 h (or untilcomplete consumption of starting material). The suspension is filtered,and the filtrate is concentrated to dryness. To the residual material isadded an aqueous solution of sodium carbonate (1M, 2 mL); and theresulting mixture is stirred for 30 min and then concentrated. Theresidue is purified by silica gel chromatography usingdichloromethane/methanol (90:10 to 80:20) as eluent to give thecorresponding 1,3-propanedisulfonic acid monoester.

d) 1,3-Propanedisulfonic Acid Monoesters (Alternate Protocol):

(R is R⁴ as previously described)

Compound C1 (Example 13) (5.0 mmol) and triethylamine (20.0 mmol) areadded to a stirred solution of selected alcohol (5.25 mmol) indichloromethane (15 mL). The resulting mixture is stirred for 24 h atroom temperature and the reaction mixture concentrated in vacuo. Theresidue is diluted with water and passed through a column of stronglyacid cation exchange resin (Dowex™ Marathon™ C, 30-40 mesh, 30 g).Elution with water permitted to isolate the monosulfonic acid prior tosilica gel chromatography. The corresponding sodium salt can also beobtained after treatment of the monosulfonic acid in methanol withaqueous 1N sodium carbonate (10.0 mmol) for 15 min. at room temperature.The mixture is then concentrated to dryness and subjected to silica gelchromatography using a mixture of dichloromethane and methanol as eluentto isolate the corresponding 1,3-propanedisulfonic acid monoester. Thefinal product can also be lyophilized as its final solid form.

e) 1,3-Propanedisulfonic Acid Diesters:

(R is R³ in one occurrence and R⁴ in another and are as previouslydescribed)

To a cold (0° C.) solution of 1,3-propanedisulfonyl dichloride from Step(a) (4.8 g, 20 mmol) in dichloromethane (30 mL) is added dropwise asolution of a corresponding alcohol (44 mmol) indichloromethane/pyridine (20 mL:5 mL). The reaction mixture is stirredfor 3-15 h while it is gradually warmed to room temperature. Aqueoushydrochloric acid (1M) is added to the reaction mixture. The organiclayer is separated, dried over magnesium sulfate and concentrated. Theresidual material is purified by silica gel column using hexanes/ethylacetate as eluent to isolate the corresponding 1,3-propanedisulfonicacid diester.

Example 2 Preparation of Compounds B1 and B2(Bis(Trifluoroacetate) Salt)

Step 1:

To a stirred solution of commercial 3-bromo-2,2-dimethylpropanol (3.5 g,21 mmol) in dimethylsulfoxide (50 mL) was added well grounded potassiumcyanide (3.8 g, 58 mmol). The reaction mixture was stirred at 100° C.for 15 h, then cooled to room temperature and diluted with 1Mhydrochloric acid. The mixture was extracted with ethyl acetate and theextracts were washed with 1M hydrochloric acid, dried over sodiumsulfate and evaporated to an oily residue. The residual material waspurified by column chromatography (silica gel, hexanes/ethyl acetate70:30 then 50:50) to afford 3.2 g of4-hydroxy-3,3-dimethylbutanenitrile. ¹H NMR (CDCl₃, 500 MHz) δ (ppm)1.01 (s, 6H), 2.00 (m, 1H), 2.31 (s, 2H), 3.36 (d, J=3.0 Hz, 2H); ¹³CNMR (CDCl₃, 125 MHz) δ (ppm) 23.89, 27.10, 35.46, 70.0, 118.83.

Step 2:

Water-wet Raney-nickel (1 g) was added to a stirred solution of4-hydroxy-3,3-dimethylbutanenitrile from Step 1 (3.0 g, 26.51 mmol) inethanol (100 mL). To this suspension was added ammonium hydroxide (30%in water, 10 mL). The reaction mixture was stirred under atmosphericpressure of hydrogen for 2 days, and then filtered. The filtrate wasconcentrated; and the resulting residue was dissolved in dichloromethane(60 mL) followed by addition of di(tert-butyl)dicarbonate (6.3 g, 29mmol). The reaction mixture was stirred at room temperature for 2 h andthen concentrated under reduced pressure. The residual material waspurified by silica gel column chromatography (hexanes/ethyl actetate80:20 then 70:30) to isolate4-t-butoxycarbonylamino-2,2-dimethyl-1-butanol (3.8 g, 66%). ¹H NMR(CDCl₃, 500 MHz) δ (ppm) 1.90 (s, 6H), 1.43 (s, 9H), 1.46 (m, 2H), 2.10(bs, 1H), 3.13 (m, 2H), 3.35 (d, J=6.0 Hz, 2H), 4.65 (bs, 1H).

Step 3:

To a stirred solution of 4-t-butoxycarbonylamino-2,2-dimethyl-1-butanolfrom Step 2 (0.43 g, 2 mmol) in pyridine (10 mL) was added1,3-propanedisulfonyl dichloride (Example 1 (a)) (812 mg, 4 mmol). Thereaction mixture was stirred at room temperature for 2 h, diluted withtoluene, and concentrated under reduced pressure. The residual materialwas diluted with ethyl acetate. The resulting solution was washed withwater, dried over sodium sulfate and concentrated. The residual materialwas purified by column chromatography (silica gel, hexane/ethyl acetate70:30 then 60:40), providing Compound B1 (1.1 g, 96% yield) as a whitesolid. ¹H NMR (CDCl₃, 500 MHz) δ (ppm) 1.00 (s, 12H), 1.44 (s, 18H),1.52 (m, 4H), 2.43 (quint, J=7.2 Hz, 2H), 3.15 (m, 4H), 3.36 (t, J=7.0Hz, 4H), 3.93 (s, 4H), 4.58 (bs, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ (ppm)18.71, 24.10, 28.65, 33.97, 36.51, 38.61, 47.95, 77.70, 79.51, 156.08;ES-MS 601 (M−1).

Step 4:

Trifluoroacetic acid (1 mL) was added to a stirred solution of CompoundB1 from Step 3 (0.22 g, 0.36 mmol) in CH₂Cl₂ (6 mL). The reactionmixture was stirred at room temperature for 2 h then concentrated underreduced pressure to afford Compound B2 (bis(trifluoroacetate) salt) inquantitative yield as a colorless waxy solid. ¹H NMR (D₂O, 500 MHz) δ(ppm) 0.88 (s, 12H), 1.55 (m, 4H), 2.25 (quint, J=7.0 Hz, 2H), 2.91 (m,4H), 3.47 (t, J=7.2 Hz, 4H), 3.95 (s, 4H); ¹³C NMR (D₂O, 125 MHz) δ(ppm) 18.00, 22.65, 33.22, 35.29, 35.73, 47.17, 78.162; ES-MS 403 (M+1).

Example 3 Preparation of Compounds A1(Potassium Salt) and A2

Step 1:

To a stirred solution of 4-t-butoxycarbonylamino-2,2-dimethyl-1-butanol(Example 2, Step 2) (0.43 g, 2 mmol) in pyridine/CH₂Cl₂ (10 mL:10 mL)was added 1,3-propanedisulfonyl dichloride (Example 1 (a)) (407 mg, 2mmol), followed by addition of 1M aqueous potassium carbonate (5 mL).The reaction mixture was vigorously stirred for 30 min then concentratedunder reduced pressure. The residual material was purified by silica gelchromatography (dichloromethane/methanol 90:10 then 80:20) to isolateCompound A1(potassium salt) (0.42 g, 49% yield) as a white solid. ¹H NMR(D₂O, 500 MHz) δ (ppm) 0.86 (s, 6H), 1.29 (s, 9H), 1.38 (m, 2H), 2.14(m, 2H), 2.93 (t, J=7.0 Hz, 2H), 2.98 (m, 2H), 3.43 (t, J=7.0 Hz, 2H),3.92 (s, 2H); ¹³C NMR (D₂O, 125 MHz) δ (ppm) 19.10, 23.08, 27.91, 33.33,36.13, 37.53, 47.84, 48.78, 78.98, 81.06, 158.28; ES-MS 402 (M-1-K).

Step 2:

Trifluoroacetic acid (1 mL) was added to a stirred solution of CompoundA1(K) from Step 1 (0.20 g, 0.47 mmol) in dichloromethane (6 mL). Thereaction mixture was stirred at room temperature for 2 h thenconcentrated under reduced pressure. The residual material was suspendedin ethanol/diethyl ether; and the resulting suspension was filtered. Thesolid material was washed with ether then dried to obtain Compound A2(0.12 g, 88% yield) as a white solid. ¹H NMR (D₂O, 500 MHz) δ (ppm) 0.88(s, 6H), 1.57 (m, 2H), 2.14 (quint, J=7.0 Hz, 2H), 2.90-2.95 (m, 4H),3.46 (t, J=7.0 Hz, 2H), 4.64 (s, 2H); ¹³C NMR (D₂O, 125 MHz) δ (ppm)19.14, 22.72, 33.18, 35.35, 35.81, 47.84, 48.67, 78.24; ES-MS 302 (M−1).

Example 4 Preparation of Compounds B3, B4(Bis(Trifluoroacetate) Salt)and B73

Step 1 and Step 2:

Using an amended version of the procedure of Example 2 (Steps 3 and 4)used for the synthesis of Compounds B1 andB2(bis(trifluoroacetate)salt), Compounds B3 (used as an intermediate)and B4(bis(trifluoroacetate)salt) were prepared by replacing4-(t-butoxycarbonylamino-2,2-dimethyl-1-butanol with commercial3-(t-butoxycarbonylamino-2,2-dimethyl-1-propanol (Steps 1 and 2).Compound B4(bis(trifluoroacetate)salt) was obtained (0.59 g) as acolorless waxy solid. ¹H (D₂O, 500 MHz) δ in ppm 0.90 (s, 12H), 2.27(quint, J=7.2 Hz, 2H), 2.88 (s, 4H), 3.48 (t, J=7.2 Hz, 4H), 4.07 (s,4H); ¹³C (D₂O, 125 MHz) δ (ppm) 17.90, 20.80, 33.92, 46.22, 47.32,76.33, 116.00 (q, J=293 Hz, CF₃ of TFA), 163.00 (q, J=36 Hz, CO of TFA);ES-MS 373 (M-1-2TFA).

Step 3:

To a suspension of Compound B4(bis(trifluoroacetate)salt) from Step 2(0.671 g, 1.5 mmol) in dichloromethane (40 mL) was added triethylamine(1.3 mL, 9.0 mmol) followed by commercial ethyl chloroformate (0.86 mL,9.0 mmol). The mixture was stirred for 2 h at room temperature, dilutedwith 1H HCl and extracted three times with ethyl acetate. The combinedorganic layers were washed with water, dried over magnesium sulfate,filtered and filtrate evaporated to give a residue. The crude productwas purified by silica gel chromatography using hexane/ethyl acetate(50:50) to isolate Compound B73 (0.46 g, 59% yield) as a colorless oil.¹H NMR (CDCl₃, 500 MHz) δ in ppm 0.975 (s, 2×6H), 1.24 (t, J=7.3 Hz,2×3H), 2.45 (quint, J=7.0 Hz, 2H), 3.12 (d, J=7.0 Hz, 2×2H), 3.39 (t,J=7.0 Hz, 2×2H), 3.97 (s, 2×2H), 4.10 (q, J=7.3 Hz, 2×2H), 4.96 (bt,2×NH).

Example 5 Preparation of Compounds A3 (Potassium Salt) and A4

Step 1:

Using an amended version of Step 1 of the procedure of Example 3, usedfor the preparation of Compound A1(potassium salt), CompoundA3(potassium salt) was prepared from commercial3-t-butoxycarbonylamino-2,2-dimethyl-1-propanol and1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound A3(potassiumsalt) was obtained (0.19 g) as a white powder. ¹H NMR (D₂O, 500 MHz) δppm 0.82 (s, 6H), 1.29 (s, 9H), 2.13 (quint, J=7.2 Hz, 2H), 2.90 (s,2H), 2.92 (t, J=7.2 Hz, 2H), 3.42 (t, J=7.2 Hz, 2H), 3.93 (s, 2H); ¹³CNMR (D₂O, 125 MHz) d 19.04, 21.22, 27.83, 35.73, 46.79, 47.84, 48.76,76.87, 81.03, 158.50; ES-MS 426 (M−1).

Step 2:

Compound A4 was prepared from Compound A3(potassium salt) from Step 2using an amended version of Step 2 of the procedure of Example 3, usedfor the preparation of Compound A2. Compound A4 was obtained (0.16 g) asa white solid. ¹H NMR (D₂O, 500 MHz) δ ppm 0.97 (s, 6H), 2.13 (quint,J=7.2 Hz, 2H), 2.89 (s, 2H), 2.95 (t, J=7.2 Hz, 2H), 3.46 (t, J=7.0 Hz,2H), 4.06 (s, 2H); ¹³C NMR (D₂O, 125 MHz) δ 19.09, 20.88, 33.90, 46.32,47.96, 48.66, 76.11; ES-MS 288 (M−1).

Example 6 Preparation of 1-Chloroethyl 2-Methylpropanoate

To a cold (0° C.) solution of isobutyryl chloride (10 mL, 98 mmol) inCH₂Cl₂ (250 mL) was added zinc chloride (1.6 g, 9.8 mmol), followed byacetaldehyde (6.5 g, 147 mmol). The reaction mixture was stirred for 4 hat room temperature then concentrated. The crude material was diluted indiethyl ether and water, and the phases obtained were separated. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography using diethyl ether/hexanes (1:10) as eluent toprovide 7.0 g of the title compound as a colorless liquid. ¹H NMR (500MHz, CDCl₃) δ in ppm 1.17-1.20 (m, 6H), 1.79 (d, J 6.0 HHz, 3H),2.51-2.61 (m, 1H), 6.54 (q, J=6.0 Hz, 1H),

Example 7 Preparation of Compounds A14, A51, A52(Sodium Salt), B14,B51(Bis(Trifluoroacetate) Salt) and B52 a) Compound A51:

Step 1:

To a mixture of commercial 3-amino-2,2-dimethyl-1-propanol (1.33 g, 13mmol) in tetrahydrofuran (40 mL) and 1 M aqueous potassium carbonate (10mL) was added a solution of N-Boc-Phe-O-Succinimide (4.60 g, 13 mmol).The reaction mixture was stirred vigorously at room temperature for 2 h.The two phases were separated and the organic layer was concentrated toafford 3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropanol as a whitesolid ready for use without further purification.

Step 2:

To a stirred solution of3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropanol from Step 1 (2 mmol)in a mixture of pyridine/dichloromethane (5 mL:10 mL) was added asolution of phenyl 3-phenoxysulfonyl-1-propanesulfonyl chloride (Example1 (b)) (2.2 mmol) in dichloromethane (5 mL). The reaction mixture wasstirred at room temperature for 15 h, then concentrated and redilutedwith ethyl acetate and aqueous hydrochloric acid (1 N). The organicphase was isolated, washed with aqueous hydrochloric acid (1N) andconcentrated. The residual material was purified by silica gelchromatography using hexanes/ethyl acetate (70:30 to 50:50) as eluent toafford 3-phenoxysulfonyl-1-propanesulfonic acid3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropyl ester.

Step 3:

To a solution of 3-phenoxysulfonyl-1-propanesulfonic acid3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropyl ester from Step 2 (1.24g, 2 mmol) in methanol (50 mL) was added acetic acid (5 mL) followed byaddition of Pd(OH)₂ (200 mg) in water (5 mL). The reaction mixture wasstirred under hydrogen atmosphere (balloon) for 2-3 h (or until completeconsumption of starting material). The suspension was filtered, and thefiltrate was concentrated to dryness. The resulting crude material wasdissolved in dichloromethane (10 mL), followed by addition oftrifluoroacetic acid (5 ml). The reaction mixture was stirred for 2 h,concentrated under reduce pressure, and purified by silica gelchromatography using dichloromethane/methanol (90:10) as eluent to yieldCompound A51 (800 mg) as a white solid. ¹H NMR (D₂O, 500 MHz) δ in ppm0.77 (s, 3H), 0.80 (s, 3H), 2.27 (quint, J=7.0 Hz, 2H), 2.95 (d, J=14.0Hz, 1H), 3.06 (t, J=7.5 Hz, 2H), 3.15 & 3.25 (ABX, J=14.0 & 8.0 Hz, 2H),3.24 (m, 1H), 3.53 (t, J=7.0 Hz, 2H), 3.97 (AB, J=9.0 Hz, 2H), 4.25 (dd,J=9.0 & 7.0 Hz, 1H), 7.31-7.44 (m, 5H), 8.05 (bt, CONH, not completelyexchanged with D₂O).

b) Compound A52(Sodium Salt):

To a stirred solution of3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropanol (Example 7 (a),Step 1) (2.0 g) in a mixture of pyridine (5 mL) and dichloromethane (40mL) was added 1,3-propanedisulfonyl dichloride (Example 1 (a)) (1.37 g).The reaction mixture was stirred at room temperature for 15 h andconcentrated under reduced pressure. The residue was purified by silicagel chromatography using hexanes/ethyl acetate (70:30) as eluant toyield 1.5 g of the monoesterification product. The product was dissolvedin tetrahydrofuran (10 mL) to which was added a 1M aqueous solution ofsodium bicarbonate (10 mL) and tetrahydrofuran (10 mL). The reactionmixture was stirred for 15 h and concentrated under reduced pressure.The residual material was purified by silica gel chromatography(dichloromethane/methanol 90:10) to isolate Compound A52(sodium salt)(0.63 g) as white solid. ¹H NMR DMSO-d₆ 500 MHz) δ ppm 0.83 (s, 6H),1.23 (s, minor rotamer, 1.3H) and 1.30 (s, major rotamer, 7.7H), 2.00(quint, J=7.0 Hz, 2H), 2.55 (t, J=7.0 Hz, 2H), 2.76 (dd, J=14.0 & 10.0Hz, 1H), 2.90 (dd, J=14.0 & 5.0 Hz, 1H), 3.0 (t, J=7.0 Hz, 2H), 3.48 (t,J=7.5 Hz, 2H), 3.86 (s, 2H), 4.18 (m, 1H), 6.95 (d, J=8.5 Hz, 1H),7.15-7.30 (m, 5H), 7.88 (t, J=6.5 Hz, 1H).

c) Compounds B51(Bis(Trifluoroacetate) Salt) and B52

Step 1:

To a stirred solution of3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropanol (Example 7 (a),Step 1) (3.50 g) in a mixture of pyridine (10 mL) and dichloromethane(50 mL) was added 1,3-propanedisulfonyl dichloride (Example 1 (a)) (1.50g). The reaction mixture was stirred at room temperature for 15 h thenconcentrated under reduced pressure. The residue was purified by silicagel chromatography using hexanes/ethyl acetate (70:30) as eluant toafford 3.5 g of Compound B52 which was used for the next step.

Step 2:

Compound B52 (3.5 g) from Step 1 was dissolved in dichloromethane (10mL) to which was added trifluoroacetic acid (5 mL). The reaction mixturewas stirred for 2 h and concentrated under reduced pressure to affordCompound B51(bis(trifluoroacetate) salt) (0.5 g) as a white solid. ¹HNMR (CD₃OD, 500 MHz) δ ppm 0.85 (s, 2×3H), 0.90 (s, 2×3H), 2.35 (quint,J=7.0 Hz, 2H), 3.00 & 3.26 (AB, J=14.0 Hz, 2×2H), 3.10 & 3.20 (ABX,J=14.0 & 7.0 Hz, 2×2H), 3.46 (t, J=7.3 Hz, 2×2H), 3.85 (AB, J=9.5 Hz,2×2H), 4.11 (t, J=7.5 Hz, 2×1H), 7.31-7.42 (m, 2×5H).

d) Compound A14:

Step 1:

Commercial N-Cbz-L-valine-O-succinimide (5.44 g, 16 mmol) was added to asolution of 4-amino-2,2-dimethyl-1-butanol (Example 2, Step 2 prior tothe di(tert-butyl)dicarbonate step) (1.06 g, 6.9 mmol) and sodiumbicarbonate (1.74 g, 20.7 mmol) in water/tetrahydrofuran 1:1 (200 mL).After 18 h of stirring, the solution was diluted with water (100 mL) andethyl acetate (200 mL). The organic layer was separated and the aqueouslayer was extracted with ethyl acetate (100 mL). The combined organiclayers were washed with brine, filtered and concentrated to dryness. Thecrude material was purified by silica gel chromatography (hexanes/ethylacetate 80:20 to 0:100 linear gradient) to afford4-(N-CBz-L-valinamido)-2,2-dimethyl-1-butanol (2.14 g, 6.11 mmol, 88%)as a white solid.

Step 2:

Following the procedure shown in Example 1(c)-Step 1,4-(N-CBz-L-valinamido)-2,2-dimethyl-1-butanol from Step 1 (1 g, 2.86mmol) is reacted with 3-phenoxysulfonyl-1-propanesulfonyl chloride(Example 1 (b)) (0.94 g, 3.2 mmol) in the presence of pyridine (2.30 mL,28.6 mmol). Following usual workup, the mixture was purified by silicagel chromatography (hexanes/ethyl acetate 70:30 to 50:50) to afford3-phenoxysulfonyl-1-propanesulfonic acid4-(N-CBz-L-valinamido)-2,2-dimethyl-1-butyl ester (1.37 g, 78%) as apale yellow oil.

Step 3:

A solution of 3-phenoxysulfonyl-1-propanesulfonic acid4-(N-CBz-L-valinamido)-2,2-dimethyl-1-butyl ester from Step 2 (1.37 g,2.22 mmol) in methanol (100 mL) was degassed with nitrogen gas, followedby addition of Pd/C (10% wet). The mixture was stirred for 24 h under 1atmosphere of hydrogen. The reaction mixture was filtered through aCelite™ pad. The filtrate was evaporated to dryness. The residualmaterial was purified by silica gel chromatography (ethanol as eluent)to afford Compound A14 (800 mg, 89% yield) as a white solid. ¹H NMR(D₂O, 500 MHz) δ in ppm 1.00 (m, 12H), 1.59 (m, 2H), 1.13 (m, 1H), 2.27(m, 2H), 3.06 (t, J=7.5 Hz, 2H), 3.26 (m, 1H), 3.34 (m, 1H), 3.57 (t,J=7.5 Hz, 2H), 3.61 (d, J=6.0 Hz, 1H), 4.07 (s, 2H).

e) Compound B14:

Step 1:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)):4-(N-CBz-L-valinamido)-2,2-dimethyl-1-butanol (2.14 g, 6.1 mmol)(Example 7 (d), Step 1) was reacted with 1,3-propanedisulfonyldichloride (Example 1 (a)) (0.740 g, 3.1 mmol) in dichloromethane (200mL) in the presence of pyridine (2.5 mL, 30.6 mmol). Solvent wasevaporated, and the residual material was purified by silica gelchromatography (hexanes/ethyl acetate 70:30 to 0:100 linear gradient) toafford 1,3-propanedisulfonic acidbis(4-(N-CBz-L-valinamido)-2,2-dimethyl-1-butyl) ester (1.73 g, 75%) asa pale yellow oil.

Step 2:

A solution of 1,3-propanedisulfonic acidbis(4-(N-CBz-L-valinamido)-2,2-dimethyl-1-butyl) ester from Step 1 (0.70g, 0.80 mmol) in EtOH (50 mL) was degassed with nitrogen gas, followedby addition of Pd/C (10% wet). The mixture was stirred for 24 h underhydrogen gas atmosphere (1 atm.). The resulting solution was filteredthrough a pad of Celite™ and the filtrate was evaporated to dryness. Theresidual material was purified by reverse phase chromatography (C18,water/methanol (0.01% ammonium hydroxide) 100/0 to 80/20) to affordCompound B14 (0.41 g, 86% yield) as a light yellow oil. ¹H NMR (DMSO,500 MHz) δ in ppm 0.77 (d, J=6.5 Hz, 6H), 0.85 (d, J=7.0 Hz, 6H), 0.93(s, 12H), 1.41 (m, 4H), 1.83 (m, 2H), 2.11 (m, 2H), 2.88 (d, J=5.0 Hz,2H), 3.10 (m, 4H), 3.51 (t, J=8.0 Hz, 4H), 3.92 (s, 4H), 7.81 (br t,J=5.0 Hz, 2H).

Example 8 Preparation of Compounds A15(Sodium Salt) to A20(Sodium Salt)and Compounds B15 to B20

a b R′ Compound (R) (S) i-Pr A15 (S) (R) i-Pr A16 (R) (S) OEt A17 (S)(R) OEt A18 (R) (S) Oi-Pr A19 (S) (R) Oi-Pr A20

a) Compound A20(Sodium Salt):

Step 1:

To a solution of (3S)-2,2-dimethyl-3-(phenylmethoxy)pent-4-en-1-ol (4.21g; prepared according to WO2009/033054, incorporated herein byreference) in dichloromethane (40 mL) was added pyridine (7.8 mL),followed by a slow addition of a solution of3-phenoxysulfonyl-1-propanesulfonyl chloride (Example 1 (b)) (6.87 g) indichloromethane (15 mL). The dark-colored solution obtained was stirredat room temperature for 18 h. The reaction mixture was diluted with 2Naqueous hydrochloric acid (100 mL) and dichloromethane (100 mL). Theaqueous layer was extracted with dichloromethane (2×100 mL). Thecombined organic layers were successively washed with 1N aqueoushydrochloric acid (100 mL) and brine:water (1:1; 100 mL), dried overmagnesium sulfate and filtered. The solvent was evaporated to give adark oil residue, which was purified by silica gel chromatography usingethyl acetate/hexane (20:80) as eluent to obtain theO1-[(3S)-3-benzyloxy-2,2-dimethyl-pent-4-enyl] O3-phenylpropane-1,3-disulfonate (7.05 g, 76% yield) as a white solid.

Step 2:

A solution of the ethenyl intermediate from Step 1 (3.98 g) indichloromethane (125 mL) was cooled to −78° C. The solution was purgedwith oxygen followed by a mixture of oxygen and ozone at the sametemperature until the solution turned slightly blue. The reaction wasfollowed by thin layer chromatography until disappearance of thestarting material. The solution was then purged with oxygen and finallynitrogen to remove residual ozone. Excess dimethylsulfide (3.0 mL) wasadded to the reaction mixture at −78° C. and stirred, over a period of 1hour, with gradual warming to room temperature. The solvents wereremoved under reduced pressure using a rotary evaporator to give theO1-[(3R)-3-benzyloxy-2,2-dimethyl-4-oxo-butyl] O3-phenylpropane-1,3-disulfonate (4.62, 100% yield) as a colorless oil. Theresidue was used for next step without further purification.

Step 3:

A solution of the aldehyde intermediate from Step 2 (4.62 g, crude) inacetone (60 mL) was cooled to 0° C. At this temperature, a freshlyprepared 2.0 M aqueous Jones-Reagent solution (5.0 mL, 10 mmol)) wasadded slowly to the stirred solution. The reaction mixture quicklyturned brown and solid formed. The reaction was stirred at 0° C. for 1hour. After the starting material was completely consumed, excessisopropanol (3.2 mL) was added at 0° C. to consume excess oxidant andthe reaction mixture was stirred for an additional hour. The reactionmixture was diluted with water (80 mL), acidified with 1N aqueoushydrochloric acid (12 mL), transferred to an evaporator andconcentrated. The aqueous residue was diluted with ethyl acetate andextracted three times with ethyl acetate. The combined organic extractswere washed with brine, dried over magnesium sulfate, filtered, and thesolvents removed under reduced pressure. The crude acid was purified bysilica gel chromatography using a mixture of hexane/ethyl acetate/aceticacid (70:30:3) as eluent to afford the(2R)-2-benzyloxy-3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfonyloxy)butanoic acid (3.0 g, 73% yield) as an oil which crystallized onstanding at +4° C. to give a white solid.

Step 4:

The (R)-carboxylic acid from Step 3 (1.23 g) was dissolved in anhydroustoluene (10 mL) and reacted with commercial 1-chloroethylisopropylcarbonate (1.15 mL) in the presence of silver carbonate (1.70g, 6.15 mmol). The reaction mixture was wrapped in aluminium foil andwell stirred at 40° C. for over 18 h. The residual solid (silver salts)was filtered using a short plug of Celite™ in a Büchner-funnel and thecake rinsed with toluene. The solvent was removed under reducedpressure. The crude material was further purified by silica gelchromatography using ethyl acetate/hexane (20:80) as eluent to give1-isopropoxycarbonyloxyethyl(2R)-2-benzyloxy-3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfon yloxy)butanoate (0.72 g, 47% yield) as an oil.

Step 5:

The (R)-ester from Step 4 (722 mg) was dissolved in a mixture ofmethanol (24 mL) and water (3 mL). To this mixture was added 20%palladium hydroxide (0.16 g) and the mixture was subjected to hydrogen(one atmosphere, balloon). The mixture was stirred at room temperaturefor 18 hours. The mixture is filtered through a pad of Celite™ and thecake rinsed with methanol. The filtrate was treated with one equivalentof 1.0N NaOH, stirred at room temperature for 5 minutes, andconcentrated under reduced pressure to give the crude product. The crudematerial was purified by silica gel chromatography using a mixture ofdichloromethane/methanol (4:1) as eluent to afford Compound A20(sodiumsalt) (0.51 g, 91% yield) as a white solid. ¹H NMR (500 MHz, DMSO) δ inppm 0.89 (d, J=5.1 Hz, 3H) & 0.95 (d, J=5.1 Hz, 3H), 1.22-1.24 (m, 6H),1.46 (d, J=5.4 Hz, 3H), 1.96-2.01 (m, 2H), 2.54 (t, J=7.1 Hz, 2H),3.41-3.52 (m, 2H), 3.87-3.93 (m, 2H), 4.06-4.09 (m, 1H), 4.76-4.82 (m,1H), 5.84 (d, J=5.6 Hz, 0.5H, OH) & 5.90 (d, J=5.6 Hz, 0.5H, OH),6.67-6.72 (m, 1H).

b) Compound A18(Sodium Salt):

Compound A18(sodium salt) is prepared using the same methodology asdescribed for Compound A20(sodium salt) (Example 8 (a)) by replacing1-chloroethyl isopropylcarbonate in Step 4 with commercially available1-chloroethyl ethylcarbonate. Compound A18(sodium salt) was obtained(0.43 g) as a white solid. ¹H NMR (500 MHz, DMSO) δ in ppm 0.89 (d,J=6.1 Hz, 3H) & 0.94 (d, J=6.1 Hz, 3H), 1.20-1.23 (m, 3H), 1.47 (dd,J=5.6 Hz, 3H), 1.95-2.01 (m, 2H), 2.54 (t, J=7.1 Hz, 2H), 3.41-3.51 (m,2H), 3.87-3.93 (m, 2H), 4.06-4.08 (m, 1H), 4.13-4.18 (m, 2H), 5.87 (d,J=5.6 Hz, 0.5H, OH) & 5.90 (d, J=5.6 Hz, 0.5H, OH), 6.67-6.72 (m, 1H).

c) Compound A16(Sodium Salt):

Compound A16(sodium salt) was prepared using the same methodology asdescribed for Compound A20(sodium salt) (Example 8 (a)) by replacing1-chloroethyl 2-isopropylcarbonate in Step 4 with 1-chloroethyl2-methylpropanoate (Example 6). Compound A16(sodium salt) was obtained(0.35 g) as a white solid. ¹H NMR (500 MHz, DMSO) δ in ppm 0.88 (d,J=7.3 Hz, 3H), 0.94 (d, J=2.2 Hz, 3H), 1.07-1.09 (m, 6H), 1.44-1.45 (m,3H), 1.95-2.01 (m, 2H), 2.50-2.57 (m, 1H+2H, partly underneat DMSO-d6),3.42-3.52 (m, 2H), 3.87-3.93 (m, 2H), 4.06-4.09 (m, 1H), 5.82 (d, J=5.6Hz, 0.5H, 0.5 OH) & 5.87 (J=5.6 Hz, 0.5H, 0.5 OH), 6.78-6.82 (m, 1H).

d) Compound A15(Sodium Salt):

Compound A15(sodium salt) was prepared using the same methodology asdescribed for Compound A16(sodium salt) by replacing in Step 1 startingmaterial (3S)-2,2-dimethyl-3-(phenylmethoxy)pent-4-en-1-ol with(3R)-2,2-dimethyl-3-(phenylmethoxy)pent-4-en-1-ol, which was preparedsimilarly from the corresponding (S)-pantolactone.

e) Compound A17(Sodium Salt):

Compound A17(sodium salt) was prepared using the same methodology asdescribed for the sodium salt of Compound A15(sodium salt) by replacing1-chloroethyl 2-methylpropanoate in Step 4 with commercially available1-chloroethyl ethylcarbonate.

f) Compound A19(Sodium Salt):

Compound A19(sodium salt) was prepared using the same methodology asdescribed for Compound A15(sodium salt) by replacing 1-chloroethyl2-methylpropanoate in Step 4 with commercial 1-chloroethylisopropylcarbonate.

g) Compounds B15 to B20:

Compound B15 to B20 are prepared following an amended version of Example8(a) to (f) used for the preparation of Compounds A15(sodium salt) toA20(sodium salt), replacing 3-phenoxysulfonyl-1-propanesulfonyl chloride(Example 1(b)) in Step 1 with 1,3-propanedisulfonyl dichloride (Example1(a)) and adjusting the molar ratio of alcohol/disulfonyl dichloridederivative to (2:1).

Example 9 Preparation of Compounds A26(Sodium Salt) and A53(Sodium Salt)a) Compound A26(Sodium Salt):

Step 1:

To a stirred 0° C. solution of(2R)-2-benzyloxy-3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfonyloxy)butanoicacid (Example 8(a), Step 3) (0.8 g) in dichloromethane (10 mL), wasadded oxalyl chloride (0.28 mL) followed by a drop ofN,N-dimethylformamide. The reaction mixture was stirred for 1 hour andconcentrated in vacuo. The resulting residue was dissolved indichloromethane (10 mL), to which was added ethanol (2 mL). The reactionmixture was stirred overnight at room temperature. The volatiles wereremoved, and the residual material was purified by silica gelchromatography (hexanes/ethyl acetate 70:30) to affordethyl(2R)-2-benzyloxy-3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfonyloxyl)butanoate(0.70 g).

Step 2:

To a stirred solution of the ethyl ester from Step 1 (0.7 g) in methanol(10 mL) was added acetic acid (2 mL) followed by Pd(OH)₂ (0.2 g) inwater (2 mL). The reaction mixture was stirred under hydrogen (balloon)for 2-3 hours (or until complete consumption of starting material). Thesuspension was filtered, and the filtrate was concentrated to dryness. A1M aqueous sodium bicarbonate solution (2.6 ml) was added and theresulting mixture was stirred for 30 min, and then concentrated. Theresidual material was purified by silica gel chromatography usingdichloromethane/ethanol (80:20) as eluent to yield the CompoundA26(sodium salt) (0.4 g) as a white solid. ¹H NMR (D₂O, 500 MHz) δ inppm 1.05 (s, 6H), 1.31 (t, J=7.0 Hz, 3H), 2.28 (quint, J=7.0 Hz, 2H),3.07 (t, J=7.0 Hz, 2H), 3.57 (t, J=7.0 Hz, 2H), 4.15 & 4.21 (AB, J=9.3Hz, 2H), 4.17 (s, 1H), 4.27 (m, 1H).

b) Compound A53(Sodium Salt):

Compound 53(sodium salt) was produced using the same procedure asdescribed for the synthesis of Compound A26(sodium salt) (Example 9 (a))by replacing ethanol in Step 1 with isopropanol to give Compound 53(sodium salt) (0.35 g) as a white solid. ¹H NMR (D₂O, 500 MHz) δ in ppm1.05 (s, 3H), 1.06 (s, 3H), 1.31 (d, J=7.0 Hz, 3H), 1.32 (d, J=7.0 Hz,3H), 2.29 (quint, J=7.0 Hz, 2H), 3.08 (t, J=7.0 Hz, 2H), 3.59 (t, J=7.0Hz, 2H), 4.14 (s, 1H), 4.16 & 4.23 (AB, J=9.5 Hz, 2H), 5.11 (hept, J=7.0Hz, 1H).

Example 10 Preparation of Compounds A13 and B13 a) Compound A13:

Step 1:

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(c), Step 1),1-(4-hydroxy-2,2-dimethyl-1-butylaminocarbonyloxy)-1-ethyl2-methylpropanoate (US published application 2005/0222431, incorporatedherein by reference) (1.0 g, 3.6 mmol) was reacted with3-phenoxysulfonyl-1-propanesulfonyl chloride (Example 1(b)) (1.20 g, 4.0mmol) in the presence of pyridine (2.93 mL, 36.4 mmol). The crudemixture obtained was purified by silica gel chromatography(hexanes/ethyl acetate 70:30 to 50:50) to afford1-[[3,3-dimethyl-4-(3-phenoxysulfonylpropylsulfonyloxyl)butyl]carbamoyloxy]ethyl2-methylpropanoate (1.65 g, 85% yield) as a pale yellow oil.

Step 2:

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(c), Step 2), starting material from Step 1 ofExample 10(a) (1.65 g, 3.09 mmol) in methanol (100 mL) was degassed withnitrogen before addition of palladium on charcoal (10% wet). The mixturewas stirred for 24 h under hydrogen gas (1 atm.). The mixture wasfiltered through Celite™ and the filtrate was concentrated under reducedpressure. The residual material was purified by silica gelchromatography (dichloromethane/methanol 100:0 to 60:40) to affordCompound A13 (1.16 g, 82% yield) as a white solid. ¹H NMR (DMSO, 500MHz) δ in ppm 0.91 (s, 6H), 1.05 (d, J=2.0 Hz, 3H), 1.07 (d, J=2.5 Hz,3H), 1.037 (d, J=5 Hz, 3H), 1.41 (t, J=8.0H, 2H), 1.99 (m, 2H), 2.50 (m,1H), 2.55 (t, J=7.5 Hz, 2H), 3.00 (m, 2H), 3.48 (dd, J=7.5, 9.5 Hz, 2H),3.86 (s, 2H), 6.65 (q, J=5.5 Hz, 1H), 7.44 (t, J=5.5 Hz, 1H).

b) Compound B13:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e):1-(4-hydroxy-2,2-dimethyl-1-butylaminocarbonyloxy)-1-ethyl2-methylpropanoate (US published application 2005/0222431) (2.60 g, 9.45mmol) was reacted with 1,3-propanedisulfonyl dichloride (Example 1(a))(1.14 g, 4.73 mmol) in dichloromethane (200 mL) in the presence ofpyridine (7.6 mL, 94.5 mmol). After evaporation, the crude product waspurified by silica gel chromatography (hexanes/ethyl acetate 80/20 to50/50) to afford Compound B13 (2.31 g, 68% yield) as a pale yellow oil.¹H NMR (CDCl₃, 500 MHz) δ in ppm 1.00 (s, 12H), 1.16 (d, J=7.0 Hz, 12H),1.45 (d, J=5.5 Hz, 6H), 1.55 (t, J=8.0 Hz, 4H), 2.43 (m, 2H), 2.53 (m,2H), 3.17-3.25 (m, 4H), 3.36 (m, 4H), 3.94 (s, 4H), 4.86 (br d, J=4.5Hz, 2H), 6.76 (q, J=5.5 Hz, 2H).

Example 11 Preparation of Compounds A29(Sodium Salt), A30(Sodium Salt),B29 and B30 a) Compound A29(Sodium Salt):

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), commercial ethyl3-hydroxy-2,2-dimethylpropanoate was reacted with Compound C1 (Example13). Compound A29(sodium salt) was obtained (4.3 g) as a white solid. ¹HNMR (D₂O, 500 MHz) δ in ppm 4.37 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.57(t, J=7.6 Hz, 2H), 3.06 (t, J=7.6 Hz, 2H), 2.26 (quintet, J=7.6 Hz, 2H),1.28 (t, overlap with a singlet at 1.275, J=7.1 Hz, 3H), 1.275 (s, 6H).

b) Compound A30(Sodium Salt):

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), commercial benzyl3-hydroxy-2,2-dimethylpropanoate was reacted with Compound C1 (Example13). Compound A30(sodium salt) was obtained (0.91 g) as white solid. ¹HNMR (D₂O, 500 MHz) δ in ppm 1.28 (s, 6H), 2.12-2.18 (m, 2H), 2.96 (t,J=7.6 Hz, 2H), 3.40 (t, J=7.3 Hz, 2H), 4.35 (s, 2H), 5.23 (s, 2H),7.42-7.46 (m, 5H).

c) Compound B29:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), commercial ethyl3-hydroxy-2,2-dimethylpropanoate was reacted with 1,3-propanedisulfonyldichloride (Example 1 (a)). Compound B29 was obtained (16.0 g) as awhite solid. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 4.23 (s, 4H), 4.17 (q,J=7.1 Hz, 4H), 3.35 (t, J=7.3 Hz, 4H), 2.37 (m, 2H), 1.273 (t, overlapwith a singlet at 1.266, 6H) 1.266 (s, 12H).

d) Compound B30:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), commercial benzyl3-hydroxy-2,2-dimethylpropanoate was reacted with 1,3-propanedisulfonyldichloride (Example 1 (a)). Compound B30 was obtained (9.0 g, 78% yield)as a white solid. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 1.29 (s, 12H), 2.21(quint, J=7.0 Hz, 2H), 3.17 (t, J=7.0 Hz, 4H), 4.22 (s, 4H), 5.15 (s,4H), 7.33-7.38 (m, 10H); MS positive mode: 602 (M+NH₄ ⁺); MS negativemode: 643 (M+AcO⁻).

Example 12 Preparation of Compounds A32(Sodium Salt) and B32

Step 1:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), commercial methyl salicylate was reactedwith 1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B32 wasobtained (1.8 g, 74% yield) as an oil. ¹H NMR (CDCl₃, 500 MHz) δ in ppm2.75 (quint, J=7.0 Hz, 2H), 2.73 (t, J=7.0 Hz, 4H), 3.91 (s, 6H),7.26-7.45 (m, 4H), 7.58 (t, J=8.0 Hz, 2H), 7.98 (d, J=7.8 Hz, 2H).

Step 2:

To a solution of Compound B32 from Step 1 (1.89 g, 4 mmol) in methanol(100 mL) was added acetic acid (10 mL) followed by Pd(OH)₂ (0.3 g) inwater (2 mL). The reaction mixture was stirred under hydrogen (1 atm.,balloon) for 3 h. The suspension was filtered, and the filtrate wasconcentrated to dryness. The residual material was dissolved in methanol(10 mL), followed by addition of 1M aqueous sodium carbonate (4 mL). Themixture was stirred for 1 h, concentrated and purified by silica gelchromatography using dichloromethane/methanol (90:10 to 80:20) as eluentto give Compound A32(sodium salt) (0.85 g, 59% yield) as a white solid.¹H NMR (D₂O, 500 MHz) δ in ppm 2.41 (quint, J=7.0 Hz, 2H), 3.10 (t,J=7.0 Hz, 2H), 3.75 (t, J=7.0 Hz, 2H), 3.94 (s, 3H), 7.45-7.55 (m, 4H),7.72 (t, J=8.0 Hz, 2H), 7.96 (d, J=7.8 Hz, 2H).

Example 13 Preparation of Compound C1

A stirred solution of 1,3-propanedisulfonic acid (30 g) in phosphorus(V)oxychloride (P(O)Cl₃, 100 ml) was heated at 100° C. for 1 h. Thereaction mixture was allowed to cool to room temperature and chloroform(300 mL) was added. The resulting solid was filtered and washed withchloroform (2×100 mL). The solid was then added to 1.4 L of a stirringice/water mixture. The solid was then filtered, washed with water (2×200mL) and dried under high vacuum to afford Compound C1 (23.3 g, 85%yield) as a white solid. ¹H NMR (D₂O, 500 MHz) δ in ppm 2.13 (m, 2H),3.01 (t, J=7.5 Hz, 4H).

Example 14 Preparation of Compounds A23(Sodium Salt) and B23 a) StartingMaterial:

Step 1:

A solution of commercial 2,2-dimethylbutyrolactone (5 mL) intetrahydrofuran (20 mL) was added dropwise to a cooled (−78° C.)solution of 1M lithium aluminum hydride in diethylether (44 mL). After 1h at −78° C., the mixture was warmed to room temperature and stirred for15 hours. The reaction was then cooled to 0° C., and ethyl acetate (10mL) was added followed by careful addition of water (10 mL). The mixturewas stirred at room temperature for 1 h. The resulting solution wasfiltered over a pad of Celite™ and the solid was washed several timeswith ethyl acetate. After evaporation, the product was purified bysilica gel chromatography (hexanes/ethyl acetate 70:30 to 0:100) toafford the desired 2,2-dimethylbutane-1,4-diol (3.18 g, 61% yield) as acolorless oil.

Step 2:

Benzoyl chloride (3.13 mL) was added to a cooled (−78° C.) solution of2,2-dimethylbutane-1,4-diol from Step 1 (3.18 g), triethylamine (7.5 mL)and 4-(dimethylamino)pyridine (0.05 g) in dichloromethane (100 mL). Themixture was then slowly warmed up to room temperature and stirredovernight. The reaction mixture was concentrated in vacuo and thecompound was purified by silica gel chromatography (hexanes/ethylacetate 95:5 to 60:40) to afford 3,3-dimethyl-4-hydroxy-1-butyl benzoate(2.6 g, 44% yield) as a colorless oil.

b) Compound B23:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), 3,3-dimethyl-4-hydroxy-1-butyl benzoate(Example 14 (a), Step 2) was reacted with 1,3-propanedisulfonyldichloride (Example 1 (a)). Compound B23 was obtained (0.65 g, 54%yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 1.08 (s, 12H);1.83 (t, J=7.0 Hz, 4H); 2.43 (m, 2H); 3.34 (t, J=7.0 Hz, 4H); 4.02 (s,4H); 4.40 (t, J=7.0 Hz, 4H); 7.44 (t, J=8.0 Hz, 4H); 7.56 (t, J=7.0 Hz,2H); 8.02 (dd, J=8.0, 1 Hz, 4H).

c) Compound A23(Sodium Salt):

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), 3,3-dimethyl-4-hydroxy-1-butyl benzoate(Example 14 (a), Step 2) was reacted with Compound C1 (Example 13).Compound A23(sodium salt) was obtained (16.8 g) as a white solid. ¹H NMR(DMSO, 500 MHz) δ in ppm 1.01 (s, 6H); 1.75 (t, J=7.0 Hz, 2H); 2.01 (m,2H); 2.57 (t, J=7.5 Hz, 2H); 3.49 (t, J=7.5 Hz, 2H); 3.97 (s, 2H); 4.36(t, J=7.0 Hz, 2H); 7.53 (t, J=8.0 Hz, 2H); 7.65 (t, J=7.5 Hz, 1H); 7.97(d, J=7.0 Hz, 2H).

Example 15 Preparation of Compounds A6(Sodium Salt) and B6

To a stirred solution of neopentyl alcohol (1.75 g) in a mixture ofpyridine (10 mL) and dichloromethane (50 mL) was added1,3-propanedisulfonyl dichloride (Example 1 (a)) (4.82 g). The reactionmixture was stirred at room temperature for 15 hours and concentrated invacuo. A 1M aqueous solution of sodium bicarbonate (20 mL) was added andthe reaction mixture was stirred for 1 h and concentrated under reducedpressure. The residual material was purified by silica gelchromatography using dichloromethane/methanol as an eluant with first, a98:2 ratio to yield Compound B6, and second, with a 80:20 ratio to yieldCompound A6(sodium salt) (0.5 g) as a white solid. ¹H NMR (D₂O, 500 MHz)δ in ppm 0.98 (s, 9H), 2.28 (quint, J=7.5 Hz, 2H), 3.08 (t, J=7.5 Hz,2H), 3.55 (t, J=7.5 Hz, 2H), 4.02 (s, 2H). Compound B6 (0.47 g) as awhite solid, ¹H NMR (CDCl₃, 500 MHz) δ in ppm 3.90 (s, 4H), 3.34 (t,J=7.0 Hz, 4H), 2.43 (q, J=7.0 Hz, 2H), 0.99 (s, 18H).

Example 16 Preparation of Compound A56(Sodium Salt)

Step 1:

To a 0° C. solution of commercial (S)-camphanic acid (1.98 g) inmethanol (50 mL), was added freshly prepared solution of diazomethane indiethyl ether until the yellow coloration persisted. The solvent wasremoved to obtain the desired ester in quantitative yield. The ester wasdissolved in THF (100 mL) to which was added slowly at 0° C., 20 mL of a1M solution of lithium aluminium hydride in tetrahydrofuran. Thereaction mixture was stirred at room temperature for 8 h, then quenchedwith aqueous hydrochloric acid (1 M) and diluted with ethyl acetate. Theorganic layer was isolated, dried over magnesium sulfate andconcentrated under vacuum. The residual material was purified by silicagel chromatography (hexanes/ethyl acetate 50:50) to isolate the desired4-(hydroxymethyl)-1,7,7-trimethyl-3-oxabicyclo[2.2.1]heptan-2-one.

Step 2:

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), the alcohol from Step 1 was reacted withCompound C1 (Example 13). Compound A56(sodium salt) was obtained (0.4 g)as a white powder. ¹H NMR (D₂O, 500 MHz) δ in ppm 0.91 (s, 3H), 0.95 (s,3H), 0.99 (s, 3H), 1.60-1.70 (m, 2H), 1.95-2.00 (m, 3H), 2.20 (m, 2H),2.30 (quint, J=7.0 Hz, 2H), 2.45 (m, 1H), 4.70 (AB, J=16.5 Hz, 2H).

Example 17 Preparation of Compounds A58, A60, A61 and G4 a) CompoundA58:

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), methyl 3-hydroxy-2,2-dimethyl-propanoate(WO 2007/053346, incorporated herein by reference) was reacted withCompound C1 (Example 13). Compound A58 was obtained (1.2 g, 48% yield)as a white solid. ¹H NMR (D₂O, 500 MHz) δ in ppm 1.26 (s, 6H), 2.40 (m,2H), 3.05 (t, J=7.5 Hz, 2H), 3.55 (t, J=7.5H, 2H), 3.74 (s, 3H), 4.35(s, 2H).

b) Compound A60(Sodium Salt):

To a solution of Compound A30(sodium salt) (0.54 g, 1.3 mmol; Example11(b)) in a 3:1 water/ethanol solution (30 mL) was added a suspension of10% Pd/C (0.12 g) in ethanol (2 mL). The resulting solution was stirredfor 30 min under hydrogen atmosphere (balloon) and filtered over a padof Celite™. The cake was washed with methanol (15 mL) and the filtratewas evaporated to dryness to afford Compound A60(sodium salt) (0.41 g,96% yield) as a white solid. ¹H NMR (DMSO, 500 MHz) δ in ppm: 1.15 (s,6H), 1.94-2.00 (m, 2H), 2.52-2.55 (t, 2H, partly masked by DMSO-d6),3.47 (t, J=7.8 Hz, 2H), 4.14 (s, 2H), 12.65 (bs, 0.75H, CO2H).

c) Compound A61:

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), ethyl2-(tert-butoxycarbonylamino)-3-hydroxy-2-methyl-propanoate (Yu S. et al.(2005), Angewandte Chemie, International Edition, 44(1), 135-138,incorporated herein by reference) was reacted with Compound C1 (Example13). The resulting mixture was treated with trifluoroacetic acid indichloromethane to afford Compound A61 (4.2 g, 52% yield) as a whitesolid. ¹HNMR (D₂O, 500 MHz) δ in ppm 1.31 (t, J=7.1 Hz, 3H), 1.64 (s,3H), 2.25 (quint, J=7.0 Hz, 2H), 3.05 (t, J=7.0 Hz, 2H), 3.62 (t, J=7.0Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 4.52 & 4.84 (AB, J=11.3 Hz, 2H).

d) Compound G4:

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), commercial2,2-bis(hydroxymethyl)propanedioate were reacted with Compound C1(Example 13). Compound G4 was obtained (0.41 g, 31% yield) as whitesolid. ¹H NMR (D₂O, 500 MHz) δ in ppm 1.30 (t, J=7.0 Hz, 6H), 2.26(quint, J=7.5 Hz, 4H), 3.06 (t, J=7.5 Hz, 4H), 3.62 (t, J=7.5 Hz, 4H),4.34 (q, J=7.0 Hz, 4H), 4.86 (s, 4H).

Example 18 Preparation of Compounds B58 to B69 a) Compound B58:

To a solution of Compound B30 (0.96 g, 1.64 mmol, Example 11 (d)) inethanol (20 mL) was added a suspension of 10% Pd/C (0.17 g) in ethanol(2 mL). The resulting solution was stirred 2 h under hydrogen atmosphere(balloon) before being filtered over a pad of Celite™. The cake waswashed with ethanol (15 mL) and the filtrate was evaporated to drynessand afforded Compound B58 (0.65 g, 98% yield) as a white solid. ¹H NMR(DMSO, 500 MHz) δ in ppm 1.16 (s, 12H), 2.05-2.12 (m, 2H), 3.50 (t,J=7.6 Hz, 4H), 4.18 (s, 4H), 12.70 (bs, 1.5H, 2×CO2H).

b) Compound B59:

To a solution of Compound B29 (1.06 g, 3.19 mmol; Example 11 (c)) andsilver carbonate (0.86 g, 3.19 mmol) in acetonitrile (25 mL) was addedchloromethylbenzoate (2.73 mL, 16.0 mmol). The mixture was stirred for 4h at 60° C. and filtered over a pad of Celite™. The cake was washed withacetonitrile (2×20 ml). The filtrate was concentrated in vacuo and theresidue was purified by silica gel chromatography (hexanes/ethyl acetate90:10 to 50:50). Compound B59 (1.30 g, 97% yield) was obtained as acolorless oil. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 1.24 (s, 6H), 1.26 (t,J=7.0 Hz, 3H), 2.39 (quint, J=7.5 Hz, 2H), 3.30 (t, J=7.0 Hz, 2H), 3.44(t, J=7.5 Hz, 2H), 4.15 (q, J=7.5 Hz, 2H), 4.19 (s, 2H), 6.07 (s, 2H),7.50 (t, J=7.5 Hz, 2H), 7.65 (t, J=7.5 Hz, 1H), 8.09 (d, J=7.0 Hz, 2H).

c) Compound B60:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), isopropyl3-hydroxy-2,2-dimethyl-propanoate (WO 2007/053346) was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B60 (0.47 g,70% yield) was obtained as a colorless oil. ¹H NMR (CDCl₃, 500 MHz) δ inppm 1.24 (d, J=6.4 Hz, 12H), 1.25 (s, 6H), 2.38 (quint, J=7.0 Hz, 2H),3.35 (t, J=7.0 Hz, 4H), 4.22 (s, 4H), 5.01 (hept, J=6.4 Hz, 2H).

d) Compound B61:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), methyl 3-hydroxy-2,2-dimethyl-propanoate(WO 2007/053346) was reacted with 1,3-propanedisulfonyl dichloride(Example 1 (a)) to afford Compound B61 (5.3 g, 85% yield) as a whitesolid. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 4.23 (s, 4H), 3.73 (s, 6H), 3.35(t, J=7.1 Hz, 4H), 2.37 (m, 2H), 1.27 (s, 12H).

e) Compound B62:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), butyl 3-hydroxy-2,2-dimethyl-propanoate(WO 2007/053346) was reacted with 1,3-propanedisulfonyl dichloride(Example 1 (a)). Compound B62 was obtained (4.5 g, 40% yield) as a whitesolid. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 4.22 (s, 4H), 4.12 (t, J=6.5 Hz,4H), 3.35 (t, J=7.0 Hz, 4H), 2.38 (m, 2H), 1.63 (m, 4H), 1.39 (m, 4H),1.28 (s, 12H), 0.94 (t, J=7.3 Hz, 6H).

f) Compound B63:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), hexyl 3-hydroxy-2,2-dimethyl-propanoate(WO 2007/053346) was reacted with 1,3-propanedisulfonyl dichloride(Example 1 (a)). Compound B63 was obtained (2.0 g, 36% yield) as acolorless oil. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 0.89 (t, J=7.0 Hz,2×3H), 1.27 (s, 2×6H), 1.30-1.35 (m, 2×6H), 1.57 (quint, J=7.5 Hz,2×2H), 2.37 (quint, J=7.0 Hz, 2H), 3.35 (t, J=7.1 Hz, 2×2H), 4.12 (t,J=7.0 Hz, 2×2H), 4.22 (s, 2×2H).

g) Compound B64:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), propyl 3-hydroxy-2,2-dimethyl-propanoate(WO 2007/053346) was reacted with 1,3-propanedisulfonyl dichloride(Example 1 (a)). Compound B64 was obtained (7.0 g, 71% yield) as a whitesolid. ¹H NMR (CDCl₃, 500 MHz) δ in ppm: 4.23 (s, 4H), 4.08 (t, J=6.6Hz, 4H), 3.35 (t, J=7.2 Hz, 4H), 2.38 (m, 2H), 1.67 (m, 4H), 1.27 (s,12H), 0.9 (t, J=7.4 Hz, 6H).

h) Compound B65:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), cyclobutyl3-hydroxy-2,2-dimethyl-propanoate (WO 2007/053346) was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B65 wasobtained (0.61 g, 44% yield) as a colorless oil. ¹H NMR (CDCl₃, 500 MHz)δ in ppm 1.26 (s, 2×6H), 1.59-1.69 & 1.79-1.85 (m, 2×(1H & 1H),2.02-2.10 (m, 2×2H), 2.32-2.40 (m, 2H+(2×2H)), 3.34 (t, J=7.1 Hz, 2×2H),4.21 (s, 2×2H), 4.98 (q, J=7.6 Hz, 2×1H).

i) Compound B66:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), isobutyl3-hydroxy-2,2-dimethyl-propanoate (WO 2007/053346) was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B66 wasobtained (3.9 g, 32% yield) as a light yellow oil. ¹H NMR (CDCl₃, 500MHz) δ in ppm 4.23 (s, 4H), 3.90 (d, J=6.6 Hz, 4H), 3.34 (t, J=7.8 Hz,4H), 2.37 (m, 2H), 1.95 (m, 2H), 1.28 (s, 12H), 0.94 (d, J=6.8 Hz, 12H).

j) Compound B67(Bis(Hydrochloride) Salt):

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), ethyl2-(tert-butoxycarbonylamino)-3-hydroxy-2-methyl-propanoate (Yu S. et al.(2005), Angewandte Chemie, International Edition, 44(1), 135-138) wasreacted with 1,3-propanedisulfonyl dichloride (Example 1 (a)). Theresulting mixture was treated with trifluoroacetic acid indichloromethane and with 1N aqueous hydrochloric acid to afford compoundB67(bis(hydrochloride) salt) (0.75 g, 49% yield) as a white solid. ¹HNMR (D₂O, 500 MHz) δ in ppm 1.31 (t, J=7.3 Hz, 2×3 H), 1.63 (s, 2×3 H),2.35 (quint, J=7.0 Hz, 2H), 3.63 (t, J=7.3 Hz, 2×2 H), 4.35 (q, J=7.3Hz, 2×2 H), 4.53 & 4.83 (AB, J=11.3 Hz, 2×2 H).

k) Compound B68:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), ethyl 3-hydroxy-2,2-dimethyl-butanoate(Boyd, V. L. et al. (1987), J. Med. Chem., 30(2), 366-374, incorporatedherein by reference) was reacted with 1,3-propanedisulfonyl dichloride(Example 1(a)). Compound B68 was obtained (0.65 g, 54% yield) as acolorless oil. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 1.17 (s, 6H); 1.25 (s,6H); 1.28 (t, J=7.0, 6H); 1.40 (d, J=6.5 Hz, 6H); 2.35 (m, 2H); 3.30 (t,J=7.0 Hz, 4H); 4.16 (m, 4H); 5.10 (q, J=6.5 Hz, 2H).

l) Compound B69:

Step 1:

To a suspension of paraformaldehyde (0.87 g, 26.4 mmol) and potassiumcarbonate (7.3 g, 52.8 mmol) in ethanol (100 mL) was addeddiethylmalonate (3 mL, 17.6 mmol). The reaction mixture was stirred atroom temperature for 24 h, filtered over a pad of Celite™, and the cakeobtained was washed with ethanol (2*20 mL). The filtrate wasconcentrated in vacuo and the residue was purified by silica gelchromatography (hexanes/ethyl acetate 90:10 to 70:30) to afford diethyl2-(hydroxymethyl)-2-methyl-propanedioate (2.8 g, 78% yield) as acolorless oil.

Step 2:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(a)), the alcohol from Step 1 was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B69 wasobtained (2.64 g, 67% yield) as a colorless oil. ¹H NMR (CDCl₃, 500 MHz)δ in ppm 1.28 (t, J=7.5 Hz, 12H); 1.55 (s, 6H); 2.36 (m, 2H); 3.35 (t,J=7.0 Hz, 4H); 4.23 (q, J=7.5 Hz, 8H); 4.54 (s, 4H)

Example 19 Preparation of Compounds A62(Sodium Salt) and A63(SodiumSalt) a) Compound A62(Sodium Salt):

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), diethyl ester(2-hydroxy-1,1-dimethylethyl)-phosphonic acid, (Cann P. F. et al.(1972), J. Chem. Soc., Perkin Transactions 2, (3), 304-311, incorporatedherein by reference) was reacted with Compound C1 (Example 13). CompoundA62(sodium salt) was obtained (0.7 g, 84% yield) as a colorless paste.¹H NMR (D₂O, 500 MHz) δ in ppm 1.23 (s, 3H), 1.28 (s, 3H), 1.35 (t,J=7.0 Hz, 6H), 2.30 (quint, J=7.2 Hz, 2H), 3.07 (t, J=7.0 Hz, 2H), 3.58(t, J=7.5 Hz, 2H), 4.2 (m, 4H), 4.28 (s, 1H), 4.32 (s, 1H).

b) Compound A63(Sodium Salt):

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), 2-methyl-2-nitro-1-propanol (Janzen, E.G. et al. (1978), J. Org. Chem (1978), 43(10), 1900-1903, incorporatedherein by reference) was reacted with Compound C1 (Example 13). CompoundA63(sodium salt) was obtained (0.5 g, 15% yield) as a white powder. ¹HNMR (D₂O, 500 MHz) δ in ppm 1.68 (s, 6H), 2.26 (quint, J=7.0 Hz, 2H),3.05 (t, J=7.0 Hz, 2H), 3.59 (t, 7.0 Hz, 2H), 4.79 (s, 2H).

Example 20 Preparation of Compounds B56 and B70 to B72 a) Compound B56:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), the alcohol from Step 1 of Example 16 wasreacted with 1,3-propanedisulfonyl dichloride (Example 1 (a)). CompoundB56 was obtained (0.32 g, 10% yield) as a colorless paste. ¹H NMR(CDCl₃, 500 MHz) δ in ppm 0.97 (s, 2×3H), 0.98 (s, 2×3H), 1.11 (s,2×3H), 1.67-1.73 (m, 2×1H), 1.83-1.89 (m, 2×1H), 2.00 (m, 2×1H), 2.08(m, 1H), 2.47 (quint, J=7.0 Hz, 2H), 3.44 (m, 2×2H), 2.48 (AB, J=11.7Hz, 2×2H).

b) Compound B70:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), the diethyl ester of(2-hydroxy-1,1-dimethylethyl)-phosphonic acid (Cann P. F. et al. (1972),J. Chem. Soc., Perkin Transactions 2, (3), 304-311) was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B70 wasobtained (0.70 g, 24% yield) as a yellow oil. ¹H NMR (CDCl₃, 500 MHz) δin ppm 1.24 (s, 2×3H), 1.27 (s, 2×3H), 1.34 (t, J=7.2 Hz, 2×6H), 2.44(quint, J=7.2 Hz, 2H), 3.39 (t, J=7.0 Hz, 2×2H), 4.16 (m, 2×4H), 4.22(s, 2×1H), 4.25 (s, 2×1H).

c) Compound B71:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), commercial3-hydroxy-2,2-dimethyl-propanenitrile was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B71 wasobtained (4.10 g, 66% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δin ppm 1.45 (s, 2×6H), 2.53 (quint, J=7.0 Hz, 2H), 3.47 (t, J=7.0 Hz,2×2H), 4.15 (s, 2×2H).

d) Compound B72:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), 2-methyl-2-nitro-1-propanol (Janzen etal. (1978), J. Org. Chem. (1978), 43(10), 1900-1903) was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B72 wasobtained (5.0 g, 62% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δin ppm 1.68 (s, 2×6H), 2.36 (quint, J=7.0 Hz, 2H), 3.36 (t, J=7.0 Hz,2×2H), 4.52 (s, 2×2H).

Example 21 Preparation of Compound A64

Step 1:

A solution of commercial 3-amino-2,2-dimethyl-1-propanol (1.7 g, 16.5mmol), N-[(1,1-dimethylethoxy)carbonyl]-D-Valine,2,5-dioxo-1-pyrrolidinyl ester (Giuntini F. et al., J. Med. Chem.(2009), 52(13), 4026-4037, incorporated herein by reference) (4.7 g,15.0 mmol) and 1M aqueous potassium carbonate (10 mL, 10.0 mmol) inacetonitrile (30 mL) was stirred at room temperature for 2 h. Themixture was concentrated to about one third of its volume, diluted with1M hydrochloric acid and extracted three times with ethyl acetate. Thecombined organic layers were washed with water, dried over magnesiumsulfate, filtered and the filtrate evaporated to a residue. The crudeproduct was purified by silica gel chromatography using hexane/ethylacetate (50:50) to isolate 4 g (88% yield) of tert-butylN-[(1S)-1-[(3-hydroxy-2,2-dimethyl-propyl)carbamoyl]-2-methyl-propyl]carbamate.

Step 2:

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), the alcohol from Step 1 (1.7 g, 5.62mmol) was reacted with Compound C1 (Example 13) (1.15 g, 6.18 mmol) togive 2.6 g (89% yield) of the intermediate sodium3-[3-[[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoyl]amino]-2,2-dimethyl-propoxy]sulfonylpropane-1-sulfonate.

Step 3:

The intermediate from Step 2 (2.6 g, 5.0 mmol) was stirred for 3 h atroom temperature in a mixture of trifluoroacetic acid (6 mL) anddichloromethane (10 mL). The mixture was evaporated to dryness to affordCompound A64 (2.3 g, 90% yield) as a white solid. ¹H NMR (D₂O, 500 MHz)δ in ppm 0.99 (s, 6H), 1.02 (d, J=7.0 Hz, 3H), 1.05 (d, J=7.0 Hz, 3H),2.22 (m, 1H), 2.28 (quint, J=7.0 Hz, 2H), 3.06 (t, J=7.0 Hz, 2H), 3.16 &3.32 (AB, J=14.0 Hz, 2H), 3.56 (t, J=7.3 Hz, 2H), 3.82 (d, J=5.9 Hz,1H), 4.06 (s, 2H), 8.34 (bt, CONH not completely exchanged with D2O).

Example 22 Preparation of Compounds A65(Sodium Salt) to A68(Sodium Salt)a) Compound A65(Sodium Salt):

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), commercial1-benzoate-2,2-dimethyl-1,3-propanediol was reacted with Compound C1(Example 13). Compound A65(sodium salt) was obtained (2.3 g, 59% yield)as white solid. ¹H NMR (D₂O, 500 MHz) δ in ppm 0.99 (s, 6H), 1.02 (d,J=7.0 Hz, 3H), 1.05 (d, J=7.0 Hz, 3H), 2.22 (m, 1H), 2.28 (quint, J=7.0Hz, 2H), 3.06 (t, J=7.0 Hz, 2H), 3.16 & 3.32 (AB, J=14.0 Hz, 2H), 3.56(t, J=7.3 Hz, 2H), 3.82 (d, J=5.9 Hz, 1H), 4.06 (s, 2H), 8.34 (bt, CONHnot completely exchanged with D2O).

b) Compound A66(Sodium Salt):

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), phosphoric acid, diethyl3-hydroxy-2,2-dimethylpropyl ester (Ogilvie et al., J. Am. Chem. Soc.(1977), 99(4), 1277-1278, incorporated herein by reference) was reactedwith Compound C1 (Example 13). Compound A66(sodium salt) was obtained(1.2 g, 27% yield) as a colorless waxy solid. ¹H NMR (D₂O, 500 MHz) δ inppm 1.03 (s, 6H), 1.33 (t, J=7.0 Hz, 6H), 2.28 (quint, J=7.0 Hz, 2H),3.07 (t, J=7.0 Hz, 2H), 3.59 (t, J=7.0 Hz, 2H), 3.92 (d, J=4.6 Hz, 2H),4.16 (s, 2H), 4.20 (m, 4H).

c) Compounds A67(Sodium Salt) and A68(Sodium Salt):

Step 1:

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), commercial2,2,5-trimethyl-1,3-dioxane-5-methanol (1.0 g, 6.24 mmol) was reactedwith Compound C1 (Example 13) (1.2 g, 6.44 mmol). Compound A67(sodiumsalt) was obtained (0.7 g, 30% yield) as a white solid. ¹H NMR (D₂O, 500MHz) δ in ppm 0.93 (s, 3H), 1.42 (s, 3H), 1.50 (s, 3H), 2.30 (quint,J=7.2 Hz, 2H), 3.07 (t, J=7.3 Hz, 2H), 3.59 (t, J=7.6 Hz, 2H), 3.78 (AB,J=12.5 Hz, 4H), 4.39 (s, 2H).

Step 2:

Compound A67(sodium salt) from Step 1 (0.70 g, 2.0 mmol) was dissolvedin water (3 mL) and diluted with acetic acid (7 mL). The mixture wasstirred for 10 h and the solvents were removed by evaporation to giveCompound A68(sodium salt) (0.5 g, 80% yield) as a white solid. ¹H NMR(D₂O, 500 MHz) δ in ppm 0.95 (s, 3H), 2.30 (quint, J=7.2 Hz, 2H), 3.07(t, J=7.3 Hz, 2H), 3.50 (AB, J=12.5 Hz, 4H), 3.57 (t, J=7.6 Hz, 2H),4.22 (s, 2H).

Example 23 Preparation of Compound B74

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), commercial1-benzoate-2,2-dimethyl-1,3-propanediol was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B74 wasobtained (0.71 g, 65% yield) as a colorless oil. ¹H NMR (CDCl₃, 500 MHz)δ in ppm 1.12 (s, 2×6H), 2.40 (quint, J=7.2 Hz, 2H), 3.32 (quint, J=7.0Hz, 2×2H), 4.13 (s, 2×2H), 4.17 (s, 2×2H), 7.46 (t, J=7.8 Hz, 2×2H),7.58 (t, J=7.0 Hz, 2×1H), 8.05 (d, J=8.5 Hz, 2×2H).

Example 24 Preparation of Compounds A69 and B75 a) Compound A69:

Step 1:

To a solution of 3,3-dimethylglutaric anhydride (3 g, 21.1 mmol) inethanol (30 mL) was added a 21% w/w solution of sodium ethoxide inethanol (5.0 mL, 23.2 mmol). After 20 h of stirring, the solution wasevaporated and the resulting solid was suspended in diethyl ether (50mL). The mixture was filtered and the solid was washed with diethylether (2×20 mL). The solid was dried under high vacuum to afford5-ethoxy-2,2-dimethyl-5-oxo-pentanoic acid sodium salt (2.92 g, 66%yield) as a light yellow solid.

Step 2:

To a solution of acid from Step 1 (2.92 g, 13.9 mmol) in a mixture ofTHF/DMF (5:1, 60 mL) was added isopropylchloroformate (211 mL, 20.9mmol). After 20 h of stirring at room temperature, the solution wascooled to 0° C. and NaBH₄ (1.06 g, 27.9 mmol) followed methanol (5 mL)was added to the solution. After 30 min of stirring, a saturated aqueoussolution of ammonium chloride was added (20 mL) and followed by ethylacetate (20 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×30 mL). The combined organic layers werewashed with brine, dried with magnesium sulfate, filtered and thefiltrate was concentrated in vacuo. The residue was purified by silicagel chromatography (hexanes/ethyl acetate 95:5 to 60:40). Afterevaporation at low temperature, ethyl 5-hydroxy-4,4-dimethyl-pentanoate(1.82 g, 75% yield) was obtained as a volatile colorless oil.

Step 3:

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), the alcohol from Step 2 was reacted withCompound C1 (Example 13). Compound A69 was obtained (1.1 g, 56% yield)as a white solid. ¹H NMR (D₂O, 500 MHz) δ in ppm 0.97 (s, 6H), 1.25 (t,J=7.0 Hz, 3H), 1.67 (t, J=8.5 Hz, 2H), 2.28 (m, 2H), 2.41 (t, J=8.0 Hz,2H), 3.07 (t, J=7.0 Hz, 2H), 3.57 (t, J=7.5 Hz, 2H), 4.06 (s, 2H), 4.14(q, J=7.0 Hz, 2H)

b) Compound B75:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), the alcohol from Step 2 of Example 24 (a)was reacted with 1,3-propanedisulfonyl dichloride (Example 1 (a)).Compound B75 was obtained (7.3 g, 57% yield) as a colorless oil. ¹H NMR(CDCl₃, 500 MHz) δ in ppm 0.98 (s, 2×6 H), 1.26 (t, J=7.1 Hz, 2×3 H),1.67 (t, J=7.0 Hz, 2×2 H), 2.30 (t, J=7.0 Hz, 2×2 H), 2.43 (quint, J=7.0Hz, 2H), 3.36 (t, J=7.10 Hz, 2×2 H), 3.93 (s, 2×2 H), 4.14 (q, J=7.10Hz, 2×2 H).

Example 25 Preparation of Compound A70(Sodium Salt)

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)),diethyl(4-hydroxy-3,3-dimethyl-butyl)phosphate (WO2006/014282,incorporated herein by reference) was reacted with Compound C1 (Example13). Compound A70(sodium salt) was obtained (0.45 g, 26% yield) as acolorless paste. ¹H NMR (D₂O, 500 MHz) δ in ppm 1.03 (s, 6H), 1.33 (t,J=7.0 Hz, 6H), 2.28 (quint, J=7.0 Hz, 2H), 3.07 (t, J=7.0 Hz, 2H), 3.56(t, J=7.0 Hz, 2H), 4.09 (s, 2H), 4.15-4.25 (m, 6H).

Example 26 Preparation of Compounds A71(Sodium Salt) to A73(Sodium Salt)a) Compound A71(Sodium Salt):

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), dihydro-3-(hydroxymethyl)-3-methyl2(3H)-furanone (US 2009/099253, incorporated herein by reference) wasreacted with Compound C1 (Example 13). Compound A71(sodium salt) wasobtained (0.42 g, 26% yield) as a white powder. ¹H NMR (D₂O, 500 MHz) δin ppm 1.32 (s, 3H), 2.22-2.32 (m, 3H), 2.54 (m, 1H), 3.06 (t, J=7.3 Hz,2H), 3.60 (dt, J=7.2 and 3.7 Hz, 2H), 4.37 & 4.46 (AB, J=10.0 Hz, 2H),4.47 (t, J=6.0 Hz, 2H).

b) Compound A72(Sodium Salt):

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)),dihydro-5-(hydroxymethyl)-5-methyl-2(3H)-furanone (US 2009/099253) wasreacted with Compound C1 (Example 13). Compound A72(sodium salt) wasobtained (0.85 g, 14% yield) as a white powder. ¹H NMR (D₂O, 500 MHz) δin ppm 1.50 (s, 3H), 2.20 (m, 1H), 2.28 (quint, J=7.3 Hz, 2H), 2.38 (m,1H), 2.77 (t, J=7.0 Hz, 2H), 3.07 (t, J=7.0 Hz, 2H), 3.60 (t, J=7.1 Hz,2H), 4.42 (AB, J=11.3 Hz, 2H).

c) Compound A73(Sodium Salt):

Following the general procedure for the synthesis of monoprotectedsulfonic acids (Example 1(d)), commercial(3R)-dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone was reacted withCompound C1 (Example 13). Compound A73(sodium salt) was obtained (0.47g, 28% yield) as a waxy solid. ¹H NMR (D₂O, 500 MHz) δ in ppm 1.11 (s,3H), 1.25 (s, 3H), 2.31-2.37 (m, 2H), 3.07 (t, J=7.6 Hz, 2H), 3.70 (t,J=7.6 Hz, 2H), 4.19-4.24 (m, 2H), 5.41 (s, 1H).

Example 27 Preparation of Compounds B76 to B81 a) Compound B76:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)),dihydro-3-(hydroxymethyl)-3-methyl-2(3H)-furanone (US 2009/099253) wasreacted with 1,3-propanedisulfonyl dichloride (Example 1 (a)). CompoundB76 was obtained (11.7 g, 79% yield) as a white solid. ¹H NMR (CDCl₃,500 MHz) δ in ppm 1.31 (s, 6H), 2.08 (ddd, J=13.2, 7.6 and 4.0 Hz, 2H),2.30-2.40 (m, 2H), 2.60 (dt, J=13.2 and 8.5 Hz, 2H), 3.36 (t, J=7.1 Hz,4H), 4.22 and 4.33 (AB, J=10.0 Hz, 4H), 4.30 (t, J=8.5 Hz, 2H), 4.40 (m,2H).

b) Compound B77:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), commercial(3R)-dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B77 wasobtained (9.3 g, 70% yield) as a white solid. ¹H NMR (D₂O, 500 MHz) δ inppm 5.01 (s, 2H), 4.11 (d, J=9.0 Hz, 2H), 4.05 (d, J=9.0 Hz, 2H),3.58-3.72 (10-peaks, 4H), 2.62 (pent, 2H), 1.29 (s, 6H), 1.18 (s, 6H).

c) Compound B78:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)),dihydro-5-(hydroxymethyl)-5-methyl-2(3H)-furanone (US 2009/099253) wasreacted with 1,3-propanedisulfonyl dichloride (Example 1 (a)). CompoundB78 was obtained (1.1 g, 57% yield) as a colorless oil. ¹H NMR (CDCl₃,500 MHz) δ in ppm 1.48 (s, 2×3H), 2.03-2.10 (m, 2H), 2.32-2.44 (m,2×2H), 2.61-2.75 (m, 2×2H), 3.40 (m, 2×2H), 4.26 (m, 2×2H).

d) Compound B79:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), commercialdihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B79 wasobtained (1.34 g, 63% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δin ppm 1.18 (s, OH) & 1.29 (s, 6H), 2.57-2.69 (m, 2H), 3.59-3.72 (m,4H), 4.05 (d, J=9 Hz, 2H) & 4.11 (d, J=9 Hz, 2H), 5.00 (s, 1H) & 5.02(s, 1H).

e) Compound B80:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), commercial(3S)-dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone was reacted with1,3-propanedisulfonyl dichloride (Example 1(a)). Compound B80 wasobtained (1.70 g, 80% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δin ppm 1.18 (s, 6H) & 1.29 (s, 6H), 2.60-2.65 (m, 2H), 3.59-3.64 (m, 2H)& 3.66-3.72 (m, 2H), 4.05 (d, J=9 Hz, 2H) & 4.11 (d, J=9 Hz, 2H), 5.00(s, 2H).

f) Compound B81:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), commercial tetronic acid was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B81 wasobtained (0.85 g, 56% yield) as a white solid. ¹H NMR (DMSO, 500 MHz) &in ppm 2.34 (m, 2H), 3.99 (t, J=7.5 Hz, 4H), 5.00 (s, 4H), 6.05 (t,J=1.5 Hz, 2H).

Example 28 Preparation of Compound P1(Disodium Salt)

Step 1:

To a solution of 1,3-propanthiol (1 mL, 10 mmol) and acrylonitrile (2mL, 30 mmol) was added Triton B (0.1 mL). The mixture was then warmed upto rt and stirred at this temperature for 20 h. The mixture wasconcentrated in vacuo and the residue was purified by silica gelchromatography (hexanes/ethyl acetate 80:20 to 0:100) to afford3-[3-(2-cyanoethylsulfanyl)propylsulfanyl]propanenitrile (2.14 g, 100%yield) as a colorless oil.

Step 2:

To a solution of disulfide from Step 1 (0.5 g, 2.34 mmol) in water (10mL) was added a 32% solution of peracetic acid in acetic acid (3.3 mL,14.0 mmol). After 4 h at room temperature, the formed solid was filteredand washed with water (2×10 mL) and ethanol (2×10 mL). The cake wasdried under high vacuum to afford 3-[3-(2-cyanoethylsulfonyl)propylsulfonyl]-propanenitrile (0.62 g, 95% yield) as a white solid.

Step 3:

To a suspension of disulfone from Step 2 (0.62 g, 2.23 mmol) in methanol(15 mL) was added a 0.5M solution of sodium methoxide in methanol (8.9mL, 4.58 mmol). After 24 h of stirring, the homogenous solution wasconcentrated in vacuo and the resulting solid was suspended in ethanol(20 mL) and the suspension was stirred 1 h at room temperature. Thesuspension was filtered and the cake washed with ethanol (2×10 mL) anddiethyl ether (2×10 mL). Water (2 mL) was added to the solid and themixture passed through a C8 pad eluting with water. The fractionscontaining Compound P1(disodium salt) were collected and lyophilized,affording Compound P1(disodium salt) (0.41 g, 85% yield) as a whitesolid. ¹H NMR (D₂O, 500 MHz) δ in ppm 1.84 (quint, J=8.0 Hz, 2H), 2.44(t, J=8.0 Hz, 4H).

Example 29 Preparation of Compounds B11 and B12 a) Compound B11:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), commercial pyridin-2-ol was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B11 wasobtained (0.59 g, 82% yield) as a colorless oil. ¹H NMR (CDCl₃, 500 MHz)δ in ppm: 2/9 (q, J=7.5 Hz, 2H), 3.98 (t, J=7.5 Hz, 4H), 7.15 (c, J=8.0Hz, 2H), 7.30 (dd, J=5.0, 7.5 Hz, 2H), 7.84 (td, J=8.0, 2.0 Hz, 2H),8.34 (dd, J=2.0, 5.0 Hz, 2H).

b) Compound B12:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(a)), pyridin-3-ol was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B12 wasobtained (0.61 g, 67% yield) as a colorless oil. ¹H NMR (DMSO, 500 MHz)δ in ppm 8.64 (d, J=2.7 Hz, 2H), 8.62 (dd, J=1.2, 4.6 Hz, 2H), 7.87(ddd, J=1.2, 2.8, 8.5 Hz, 2H), 7.58 (dd, J=4.6, 8.5 Hz, 2H), 3.85 (t,J=7.5 Hz, 4H), 2.49-2.40 (m, 2H).

Example 30 Preparation of Compounds B82 to B87 a) Compound B82:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), ethyl 2-hydroxy-3,3-dimethyl-butanoate(Wang et al. (2006), Synlett 2006(8), 1169-1172, incorporated herein byreference) was reacted with 1,3-propanedisulfonyl dichloride (Example 1(a)). Compound B82 was obtained (2.0 g, 82% yield) as a colorless oil.¹H NMR (CDCl₃, 500 MHz) δ in ppm 1.06 (s, 2×9H), 1.32 (t, J=7.0 Hz,2×3H), 2.53 (quint, J=7.0 Hz, 2H), 3.44 (t, J=7.0 Hz, 2×2H), 4.27 (m,2×2H), 4.66 (s, 2×1H).

b) Compound B83:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), ethyl 2-hydroxy-3-methyl-butanoate (Anandet al. (1994), Syn. Comm., 24(19), 2743-2747, incorporated herein byreference) was reacted with 1,3-propanedisulfonyl dichloride (Example 1(a)). Compound B83 was obtained (0.85 g, 73% yield) as a colorless oil.¹H NMR (CDCl₃, 500 MHz) δ in ppm 0.97 (d, J=6.8 Hz, 2×3H), 1.08 (d,J=7.0 Hz, 2×3H), 1.30 (t, J=7.0 Hz, 2×3H), 2.33 (m, 2H), 2.57 (m, 2×1H),3.49 (m, 2×2H), 4.27 (q, J=7.0 Hz, 2×2H), 4.88 (d, J=4.0 Hz, 2×1H).

c) Compound B84:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), 2-hydroxy-3,3-dimethyl-butanenitrile wasreacted with 1,3-propanedisulfonyl dichloride (Example 1 (a)). CompoundB84 was obtained (4.4 g, 56% yield) as a white solid. ¹H NMR (CDCl₃, 500MHz) δ in ppm 1.15 (s, 2×9H), 2.55 (quint, J=7.0 Hz, 2H), 3.52 (t, J=7.0Hz, 2×2H), 4.86 (s, 2×1H).

d) Compound B85:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), ethyl(2S)-2-hydroxy-3-methyl-butanoate(WO2008/087560, incorporated herein by reference) was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound B85 wasobtained (8.2 g, 71% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δin ppm: 0.97 (d, J=6.8 Hz, 2×3H) & 1.08 (d, J=6.8 Hz, 2×3H), 1.31 (t,J=7.1 Hz, 2×3H), 2.30-2.36 (m, 2H), 2.54-2.60 (m, 2×1H), 3.46-3.52 (m,2×2H), 4.23-4.30 (m, 2×2H), 4.89 (d, J=3.9 Hz, 2×1H).

e) Compound B86:

Compound B77 (8.6 g; Example 27 (b)) was dissolved in 2M ammonia inethanol (150 mL). The solution was stirred at room temperature for 48 h.The solvent was removed under vacuum and the residual material waswashed with hexanes (2×100 mL) to give the crude product (5 g) which wasrecrystallized from methanol. After overnight standing at roomtemperature, the solid was filtered and washed with cold methanol toafford Compound B86 (2.4 g, 25% yield) as a white solid. ¹H NMR (DMSO,500 MHz) δ in ppm 0.89 (s, 6H), 0.91 (s, 6H), 2.21 (m, 2H), 3.20 (m,2H), 3.26 (m, 2H), 3.47 (t, J=7.5 Hz, 4H), 4.69 (s, 2H), 4.83 (t, J=4.5Hz, 2H), 7.43 (brs, 2H), 7.58 (brs, 2H).

f) Compound B87:

Following the general procedure for the synthesis of diprotectedsulfonic acids (Example 1(e)), ethyl 2-hydroxy-2-methyl-propanoate wasreacted with 1,3-propanedisulfonyl dichloride (Example 1(a)). CompoundB87 was obtained (0.85 g, 53% yield) as a colorless oil. ¹H NMR (CDCl₃,500 MHz) δ in ppm 1.32 (t, J=7.0 Hz, 2×3H), 1.73 (s, 2×6H), 2.50 (quint,J=7.0 Hz, 2H), 3.46 (t, J=7.0 Hz, 2×2H), 4.27 (q, J=7.0 Hz, 2×2H).

Example 31 General Synthetic Protocol for the Synthesis of OxomethylDisulfonate Esters a) 1,3-Propanedisulfonic Acid Disilver Salt:

To a solution of 1,3PDS (109 g, 534 mmol) in H₂O (500 mL) was addedsilver carbonate (162 g, 587 mmol) in portion over 30 min. After 30 minat room temperature, the solution was filtered over a pad of Celite™ andthe cake was washed once with water (100 mL). After evaporation of thesolution on the rotavap, the solid was suspended in ethanol (500 mL) andthe resulting mixture was stirred for 30 min at room temperature andfiltered. The cake was washed twice with ethanol (2×150 mL) and driedunder vacuum at 40° C. to afford 1,3-propanedisulfonic acid disilversalt (1,3PDS(2Ag)) (198 g, 89% yield) as a white solid.

b) 1,3-Propanedisulfonic Acid Oxomethyl Diesters:

To a suspension of 1,3-propanedisulfonic acid disilver salt from Step(a) in acetonitrile is added the selected chloromethylacetate (5 eq).The mixture is heated for 24 h at 60° C. before being cooled down toroom temperature and filtered over a pad of Celite™. The cake is thenwashed with acetonitrile and the filtrate is evaporated on the rotavap.The residue is purified by silica gel chromatography to afford thecorresponding 1,3-propanedisulfonic acid oxomethyl diester.

Example 32 Preparation of Compounds D1 to D8 a) Compound D1:

Following the general procedure for the synthesis of oxomethyldisulfonate esters (Example 31 (b)), commercial chloromethylpivaloatewas reacted with 1,3-propanedisulfonic acid disilver salt (Example 31(a)). Compound D1 was obtained (18.3 g, 81% yield) as a white solid. ¹HNMR (CDCl₃, 500 MHz) δ in ppm 1.25 (s, 18H), 2.42 (quint, 7.0 Hz, 2H),3.41 (t, J=7.0 Hz, 4H), 5.81 (s, 4H).

b) Compound D2:

Following the general procedure for the synthesis of oxomethyldisulfonate esters (Example 31 (b)), commercial chloromethylbenzoate wasreacted with 1,3-propanedisulfonic acid disilver salt (Example 31 (a)).Compound D2 was obtained (0.40 g, 71% yield) as a white solid. ¹H NMR(CDCl₃, 500 MHz) δ in ppm 2.40 (quint, 7.0 Hz, 2H), 3.40 (t, J=7.0 Hz,4H), 6.02 (s, 4H), 7.49 (dt, J=8.0, 1.5 Hz, 4H), 7.64 (tt, J=9.0, 1.5Hz, 2H), 8.08 (td, 8.5, 1.5 Hz, 4H).

c) Compound D3:

Following the general procedure for the synthesis of oxomethyldisulfonate esters (Example 31 (b)), chloromethylbutanoate (Baudy et al.(2009), J. Med. Chem. 52(3), 771-778, incorporated herein by reference)was reacted with 1,3-propanedisulfonic acid disilver salt (Example 31(a)). Compound D3 was obtained (10.8 g, 76% yield) as colorless oil. ¹HNMR (CDCl₃, 500 MHz) δ in ppm 0.98 (t, J=7.5 Hz, 6H), 1.70 (m, 4H), 2.42(m, 6H), 3.41 (t, J=7.0 Hz, 4H), 5.81 (s, 4H).

d) Compound D4:

Following the general procedure for the synthesis of oxomethyldisulfonate esters (Example 31 (b)), commercialchloromethylisopropylcarbonate was reacted with 1,3-propanedisulfonicacid disilver salt (Example 31 (a)). Compound D4 was obtained (0.98 g,95% yield) as a colorless oil. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 1.35 (d,J=6.5 Hz, 12H), 2.43 (quint, J=7.0 Hz, 2H), 3.43 (t, J=7.0 Hz, 4H), 4.97(m, 2H), 5.81 (s, 4H).

e) Compound D5:

Following the general procedure for the synthesis of oxomethyldisulfonate esters (Example 31 (b)), chloromethylcyclohexanecarboxylate(Baudy et al. (2009), J. Med. Chem. 52(3), 771-778) was reacted with1,3-propanedisulfonic acid disilver salt (Example 31 (a)). Compound D5was obtained (25.0 g, 72% yield) as a white solid. ¹H NMR (CDCl₃, 500MHz) δ in ppm 1.23-1.35 (m, 6H), 1.46 (m, 4H), 1.66 (m, 2H), 1.77 (m,4H), 1.94 (m, 4H), 2.41 (m, 4H), 3.40 (t, J=7.5 Hz, 4H), 5.81 (s, 4H).

f) Compound D6:

Following the general procedure for the synthesis of oxomethyldisulfonate esters (Example 31 (b)), chloromethyl2,2-dimethylbutenoate(Baudy at al. (2009), J. Med. Chem. 52(3), 771-778) was reacted with1,3-propanedisulfonic acid disilver salt (Example 31 (a)). Compound D6was obtained (2.0 g, 66% yield) as a colorless oil. ¹H NMR (CDCl₃, 500MHz) δ in ppm 0.86 (t, J=7.5 Hz, 6H); 1.21 (s, 12H); 1.61 (q, J=7.5 Hz,4H); 2.42 (quint, J=7.0 Hz, 2H); 3.41 (t, J=7.0 Hz, 4H); 5.81 (s, 4H).

g) Compound D7:

Following the general procedure for the synthesis of oxomethyldisulfonate esters (Example 31 (b)), chloromethylpropanoate (Baudy etal. (2009), J. Med. Chem. 52(3), 771-778) was reacted with1,3-propanedisulfonic acid disilver salt (Example 31 (a)). Compound D7was obtained (13.2 g, 66% yield) as a white solid. ¹H NMR (CDCl₃, 500MHz) δ in ppm 1.91 (t, J=7.5 Hz, 6H); 2.42 (quint, J=7.0 Hz, 2H); 2.47(q, J=7.5 Hz, 4H); 3.41 (t, J=7.0 Hz, 4H); 5.82 (s, 4H).

h) Compound D8:

Following the general procedure for the synthesis of oxomethyldisulfonate esters (Example 31 (b)), chloromethylpentanoate (Baudy etal. (2009), J. Med. Chem. 52(3), 771-778) was reacted with1,3-propanedisulfonic acid disilver salt (Example 31 (a)). Compound D8was obtained (1.8 g, 57% yield) as a white solid. ¹H NMR (CDCl₃, 500MHz) δ in ppm 0.93 (t, J=7.5 Hz, 6H); 1.37 (m, 4H); 1.65 (quint, J=7.0Hz, 4H); 2.39-2.45 (m, 6H); 3.41 (t, J=7.0 Hz, 4H); 5.81 (s, 4H).

Example 33 Preparation of Compound C2

To a refluxing suspension of 1,3-propanedisulfonic acid disilver salt(Example 31 (a)) (60 g, 140 mmol) in acetonitrile (1 L) was added asolution of diiodomethane (17 mL, 210 mmol) in acetonitrile (20 mL) over15 h (syringe pump). After the addition was completed, the mixture wasrefluxed for an additional 24 h, cooled down to room temperature andfiltered over a pad of Celite™. The cake was washed with acetonitrile(2*100 mL) and the filtrate was concentrated in vacuo to about 150 mL.To this solution, 40 g of silica gel was added and the mixture wasevaporated to dryness. The residue was loaded on a silica gel column andeluted with hexanes/ethyl acetate 80:20 to 50:50 to afford Compound C2(22.6 g, 73% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δ in ppm2.54 (m, 2H), 3.60 (t, J=6.0 Hz, 4H), 5.80 (s, 2H).

Example 34 Preparation of Compound C3

To a solution of commercial diethyl 2,2-bis(hydroxymethyl)propanedioate(0.91 g, 4.15 mmol) and pyridine (1.7 mL, 20.7 mmol) in dichloromethane(200 mL) was added 1,3-propanedisulfonyl dichloride (Example 1 (a)) (1g, 4.15 mmol). The solution was refluxed for 3 days and concentrated invacuo. The residue was purified by silica gel chromatography(hexanes/ethyl acetate 90:010 to 50:50) to afford Compound C3 (0.32 g,20% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 1.31 (t,J=7.0 Hz, 6H), 2.46 (m, 2H), 3.45 (m, 4H), 4.30 (q, J=7.0 Hz, 4H), 4.66(s, 4H).

Example 35 General Synthetic Protocol for the Synthesis ofDisulfonamides

1,3-Propanedisulfonyl dichloride (Example 1(a)) (20 mmol) is added to astirred solution of selected amine (40 mmol)) in a mixture of pyridine(10 mL) and dichloromethane (50 mL). The reaction mixture is stirred atroom temperature for 15 h and then concentrated in vacuo. The residualmaterial is purified by silica gel chromatography using a mixture ofdichloromethane/methanol as eluant to yield the correspondingdisulfonamide.

Example 36 Preparation of Compounds N12 and N14 a) Compound N12:

Following the general procedure for the synthesis of disulfonamides(Example 35), commercial 3,5-dimethylpyrazole was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound N12 wasobtained (0.73 g, 68% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δppm 5.98 (s, 2H), 3.54 (t, J=7.0 Hz, 4H), 2.47 (s, 6H), 2.25 (s, 6H),2.15 (q, J=7.0 Hz, 2H).

b) Compound N14:

Following the general procedure for the synthesis of disulfonamides(Example 35), commercial imidazole was reacted with1,3-propanedisulfonyl dichloride (Example 1 (a)). Compound N14 wasobtained (0.45 g, 53% yield) as a beige solid. ¹H NMR (DMSO, 500 MHz) δppm 8.18 (s, 2H), 7.64 (s, 2H), 7.16 (s, 2H), 3.83 (t, J=7.5 Hz, 4H),1.78 (q, J=7.5 Hz, 2H).

Example 37 Preparation of Compounds N15 and N16

Step 1:

Following the general procedure for the synthesis of disulfonamides(Example 35), commercial ethyl ester L-phenylalanine hydrochloride (1.8g, 8.0 mmol) was reacted with 1,3-propanedisulfonyl dichloride (Example1 (a)) (0.964 g, 4.0 mmol). Compound N15 was obtained (0.6 g, 28% yield)as an oil. ¹H NMR (CDCl₃, 500 MHz) δ in ppm 1.25 (t, J=7.0 Hz, 6H), 2.04(m, 2H), 2.73 (m, 2H), 2.91 (m, 2H), 3.04 & 3.14 (ABX, J=14.0 & 5.7 Hz,4H), 4.18 (m, 4H), 4.34 (m, 2H), 5.07 (d, J=9.3 Hz, 2H), 7.17-7.32 (m,10H).

Step 2:

To a solution of Compound N15 from Step 1 (0.60 g, 1.1 mmol) in ethanol(10 mL) was added 6N aqueous hydrochloric acid (20 mL) and the mixturewas stirred under reflux for 4 h. The mixture was cooled, evaporated todryness and diluted in a 95:5 mixture of dichloromethane/methanol forpurification by silica gel chromatography. Elution with a mixture ofethyl acetate/acetic acid (97:3) permitted to isolate Compound N16 (0.31g, 57% yield) as a white solid. ¹H NMR (DMSO, 500 MHz) δ in ppm 1.64(quint, J=7.0 Hz, 2H), 2.47 (m, 2H), 2.60 (m, 2H), 2.78 (dd, J=13.5 &9.5 Hz, 2H), 3.05 (dd, 13.5 & 5.5 Hz, 2H), 3.98 (m, 2H), 7.20-7.32 (m,10H), 7.80 (d, J=9.0 Hz, 2H), 13.00 (bs, 2H).

Example 38 Preparation of Compounds N17 andN18(Bis(Trifluoroacetate)Salt)

Step 1:

To a stirred solution of 1,3-propanedisulfonyl dichloride (Example 1(a)) (1.5 g, 6.2 mmol) in tetrahydrofuran (30 mL) was added 28% ammoniumhydroxide (6 mL). The reaction was exothermic and was stirred for anadditional hour at room temperature. The mixture was concentrated undervacuum, dissolved in a minimum amount of water/methanol, mixed withsilica gel and evaporated to dryness. The silica gel support was appliedon top of column for silica gel chromatography using as eluent a mixtureof dichloromethane/methanol (70:30) to afford Compound N17 (0.30 g, 24%yield) as a white powder. ¹H NMR (D₂O, 500 MHz) δ in ppm 2.19 (quint,J=7.0 Hz, 2H), 3.28 (t, J=7.0 Hz, 4H).

Step 2:

To a solution of Compound N17 from Step 1 (0.303 g, 1.5 mmol) in DMF (20mL) were added commercialN-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine,2,5-dioxo-1-pyrrolidinyl ester (1.2 g, 3.3 mmol) and DBU (0.49 mL, 3.3mmol). The mixture was stirred for 15 h, diluted with ethyl acetate and1N HCl, and extracted three times with ethyl acetate. The combinedorganic layers were washed with water, dried over magnesium sulfate,filtered and filtrate concentrated in vacuo. The residue was purified bysilica gel chromatography using hexanes/ethyl acetate (50:50) to isolatethe desired tert-butylN-[1-benzyl-2-[3-[[2-(tert-butoxycarbonylamino)-3-phenyl-propanoyl]sulfamoyl]propylsulfonylamino]-2-oxo-ethyl]carbamate(0.9 g, 87% yield).

Step 3:

To a solution of intermediate from Step 2 (0.90 g, 1.3 mmol) indichloromethane (10 mL) was added trifluoroacetic acid (5 mL). Themixture was stirred at room temperature for 5 h and concentrated todryness. Trituration using an ether/hexanes mixture allowed to isolateCompound N18(bis(trifluoroacetate)salt) (0.68, 72% yield) as a whitesolid. ¹H NMR (D₂O, 500 MHz) δ in ppm 2.01 (quint, J=7.0 Hz, 2H), 3.06 &3.15 (ABX, J=14.0 & 7.0 Hz, 4H), 3.29-3.42 (m, 4H), 4.07 (t, J=7.0 Hz,2H), 7.15-7.30 (m, 10H).

Example 39 In Vitro Stability of the Compounds of the Invention a) Waterand Simulated Gastric Fluid Stability

The objective of this test was to determine the stability of theprodrugs in simulated gastric fluid (SGF) and water at 37° C. up to 2hours and in water at room temperature up to 24 hours. The stability wasperformed as indicated in Table 1.

TABLE 1 Temperatures and Sampling Summary Time-Points dH₂O at room(hours) SGF at 37° C. dH₂O at 37° C. temperature 0 Yes No Yes 1 Yes YesNo 2 Yes Yes No 24 No No Yes

Simulated gastric fluid and water samples were incubated in a shakingwater bath at 37° C. for up to 2 hours. The compound (prodrug) was addedat Time-point 0. At each selected time point (refer to table), samplealiquots were withdrawn and analyzed to determine the concentration of1,3-propanedisulfonic acid (1,3PDS). The concentrations of 1,3PDS werecalculated based on their respective peak area. The % appearance of1,3PDS was determined by the amounts of compound determined at each timepoint compared to nominal concentration (100%) of 1,3PDS generated by100% of the prodrug (equivalent concentration).

i) Simulated Gastric Fluid Preparation:

Amounts of 0.2 g of sodium chloride and 0.32 g of pepsin were weightedand transferred into a 100-mL volumetric flask. Approximately 50 mL ofdeionized water was added and the mixture well mixed. A volume of 700 μLof hydrochloric acid was added, and the volume completed to 100 mL withdeionized water. The resulting mixture was transferred in apolypropylene bottle and pH measured (pH=1.5).

ii) Sample Preparation:

A fresh stock solution at approximately 2 mg/mL of the compound wasprepared. One stability solution at 200 μg/mL in the SGF was prepared(sample referred to as Tube A). A stability solution at 200 μg/mL indeionized water was prepared (sample referred to as Tube B). Immediatelyafter preparation, each 200 μg/mL solution was diluted in triplicates to20 μg/mL in deionized water and analyzed using LC-MS/MS method(Time-point 0). Thereafter, the incubation of tubes A and B wascontinued in the shaking water bath at 37° C. for 1 and 2 hours whileone aliquot of tube B was kept at room temperature for 24 hours. At eachspecific time point of incubation, 3 aliquots (triplicate) of 50 μL wereremoved, diluted in 450 μL of water and analyzed using LC-MS/MS method.In parallel, 3 reference samples of 1,3PDS at 100, 10 and 1 μg/mL wereprepared, diluted in triplicate in water and injected at the beginningand at the end of the batch. These samples were considered as referencesamples.

iii) Evaluation:

The concentrations of 1,3PDS were calculated based on response of thereference samples and their respective peak area response. The %appearance of 1,3PDS was determined by the amounts of compounddetermined at each time point compared to expected nominal concentration(100%) of 1,3PDS generated by 100% of the prodrug (equivalentconcentration). The results of water stability are presented in Table 2and simulated gastric fluid are presented in Table 3.

TABLE 2 Water Stability Results Conversion to 1,3PDS (%) ID No 0 h 1 h 2h 24 h A6(Na) 0.4 1.0 1.6 1.4 A13 0.0 0.0 0.0 0.0 A14 0.2 0.4 1.4 —A18(Na) 12.8 23.0 28.4 15.8 A26(Na) 3.1 5.9 8.6 10.0 A32(Na) 0.0 0.1 0.10.0 A51 13 14 18 — A52(K) 7.0 14.6 18.8 21.3 B13 0.3 0.4 0.4 — B14 0.00.0 0.0 — B23 0.0 0.0 0.0 0.0 B30 0.0 0.0 0.0 0.0 C1 50.3 57.3 63.1 61.2

TABLE 3 Simulated Gastric Fluid Stability Results Conversion to 1,3PDS(%) ID No 0 h 1 h 2 h A6(Na) 0.3 1.0 1.6 A13 0.0 0.0 0.0 A14 0.2 0.3 0.4A18(Na) 2.2 3.8 4.8 A26(Na) 2.7 5.8 8.4 A32(Na) 0.0 0.0 0.0 A51 11 11 13A52(K) 6.2 13.1 15.9 B13 0.1 0.2 0.2 B14 0.0 0.0 0.0 B23 0.0 0.0 0.0 B300.0 0.0 0.0 C1 51.2 59.8 65.9

b) Whole Blood Stability:

The objective of this test was to determine the stability of theprodrugs in fresh human whole blood at different time-points (0, 0.5, 1,4, 24 hours). Blood samples were incubated in a shaking water bath at37° C. for up to 24 hours. The compound (prodrug) was added atTime-point 0, and sample aliquots were withdrawn and analyzed at eachtime point to determine the concentration of 1,3PDS. If possible, theloss of compound was determined by the amounts of compound determined ateach time point compared to the amount determined at Time-point 0. Toeliminate the conversion due to the matrix, a special Time-point 0 wasprepared in pre-extracted blood sample.

i) Sample Preparation:

Approximately 2.5 mL of whole blood was incubated in a gently shakingwater bath at 37° C. for 15 minutes. Two (2) mL of the pre-incubatedwhole blood were aliquoted in an eppendorf tube. A 100 μL aliquot ofblood was removed and 100 μL of the compound Stock Solution was added.The solution was mixed by inversion. This sample was referred to as TubeA. The final concentration of the compound in tube A was approximatelyat 100 μg/mL. Immediately after mixing, 100 μL of Tube A was aliquottedinto 3 different eppendorf tubes. These samples were extracted asdescribed in the “Extraction Procedure” Section. These samples werereferred to Time-point 0. Thereafter, the incubation of Tube A wascontinued in the shaking water bath at 37° C. for 0.5, 1, 4 and 24hours. At each specific time point of incubation, aliquots (triplicate)of 100 μL were removed and extracted as described in the “ExtractionProcedure” Section. To avoid potential further degradation of compoundand/or possible degradation products, the aliquot extracts were kept onice until analysis. After extraction, samples were analyzed usingLC-MS/MS method.

ii) Extraction Procedure:

A volume of 300 μL of cold-ice acetonitrile was added to a 1.5 mLeppendorf tube and kept on ice until utilization. 100 μL of the sampleto be extracted was added and the mix was vortexed (acetonitrile andblood). The sample was centrifuged at 16250×g (13200 rpm on IECcentrifuge with eppendorf rotor) for 5 minutes. A volume of 250 μL ofthe supernatant was transferred to another tube and evaporated todryness under a nitrogen stream. The residue was reconstituted with themobile phase. This sample was then analyzed according to 1,3PDS specificmethods.

iii) Evaluation:

The concentrations of 1,3PDS were calculated based on the nominalconcentration of the calibration standards and their respective peakarea ratio. A linear regression using a weight of 1/x² is used to derivethe concentration of 1,3PDS. The % appearance of 1,3PDS was determinedby the amounts of compound determined at each time point compared tonominal concentration (100%) of 1,3PDS generated by 100% of the prodrug(equivalent concentration). The results obtained are summarized in Table4 below.

TABLE 4 Human Whole Blood Stability Results Conversion to 1,3PDS (% bymolar ratio) ID No 0 h 0.5 h 1 h 4 h 24 h A6(Na) 0.5 0.7 0.8 1.2 4.7 A1312.8 44.0 47.8 61.7 62.3 A14 1.6 2.5 3.0 5.8 23.3 A18(Na) 9.5 16.4 18.339.8 71.9 A26(Na) 11.1 12.2 14.5 14.5 31.6 A32(Na) 0.1 0.1 0.2 0.4 2.0A51 23.7 21.8 26.5 34.4 63.6 A52(K) 21.7 24.4 29.0 32.8 55.6 B13 5.5106.1 91.1 67.0 73.2 B14 0.1 5.0 17.0 44.9 55.1 B23 1.2 103.4 98.5 59.066.5 B30 BLLQ 0.1 0.2 2.0 15.0 C1 AULQ AULQ AULQ AULQ AULQ BLLQ: Belowlower limit of quantitation AULQ: Above upper limit of quantitation

In summary, the stability results showed that the compounds act asprodrugs and liberate 1,3PDS either in gastric fluid or in whole blood.In fact most of them were found to be cleaved in whole blood to agreater extent than in gastric fluid or water, even some released 1,3PDSonly in whole blood while being relatively stable in water and simulatedgastric fluids.

Example 40 Preparation of Dosing Formulation a) Dosing Vehicle forFormulation:

Double processed tissue culture water (Sigma, W3500) was used for allthe formulation prepared in water. The vehicle 0.5% Methocel™ (Methocel™K4M, Dow Chemical, #002891) in water (double processed tissue culturewater) used for preparation of all Methocel™ formulations was preparedaccording to literature procedures. The 2% benzyl alcohol in corn oilwas prepared by adding benzyl alcohol to corn oil according toproportions, which was used for the preparation of oil formulation ofprodrugs.

b) Dosing Formulation Concentration:

For 1,3PDS(2Na), the concentration in the dosing formulation wasstandardized to such a level that the dose would be 100 mg/kg (or 0.4mmol/kg) for in vivo protocol specified dosing volume in a particularanimal species. For a prodrug, the weight of sample in the dosingformulation varied based on molecular weight in such a way thatequimolar dose (0.4 mmol/kg) for all the prodrugs would be administeredwhen given same volume of dosing formulation to the animals. The dosingvolume used for was 10 mL/kg for rats and monkeys, and 5 mL/kg forferrets; or the concentration of dosing formulation was 0.04 mmol/mL forrats and monkeys, and 0.08 mmole/mL for ferrets. The vehicles used caneither be water, 0.5% Methocel™ in water or 2% benzyl alcohol in cornoil. The dosing solution can either be a solution, a suspension or anemulsion. For different levels of doses, the amounts of the compoundsused in the dosing formulation preparation were adjusted accordingly.

c) Dosing Formulation Preparation:

For compounds soluble in the selected vehicle, the appropriate amountwas added to a stirring solution of vehicle. The mixture was prepared 30min prior dosing.

For compound insoluble in the selected vehicle, suspension (for solid)or emulsion (for oil) was prepared using a planetary micro mill(Pulverisette 7, Fritsch). The vehicles used are either 0.5% Methocel™in water or 2% benzyl alcohol in corn oil. The appropriate amount ofcompound was added, in portion, to the selected vehicle and the mixturewas processed using the planetary micro mill for 10 min at 800 rpm. Theobtained suspension or emulsion was kept under stirring using a stirringbar until dosing. The mixture could be prepared 30 min to 18 h priordosing.

Example 41 In Vivo Protocols a) PK Study in Rats

One group of four male Sprague-Dawley rats of age 7-9 weeks (body weightof 200-300 g) were fasted for 15 to 17 h before being dosed through oralgavage administration with the dosing solution/suspension prepared fromtest compounds according to Example 40 at a dose specified in Table 5 ina concentration adjusted to a dosing volume of 10 ml/kg-body weight.Food was supplied two hours post dose. Blood samples (200 μL blood) werecollected into Sarstedt micro tubes (EDTA K₃E/0.5 mL) from the jugularvein of each animal (4 animals/group) at pre-dose and at the followingtime-points of post-dose: 15 min., 30 min., 1 h, 2 h, 4 h, 6 h, 8 h, 12h, and 24 h. The collected blood samples were kept on ice and thencentrifuged at 4° C. at a minimum speed of 3000 rpm (1620G) for 10 minto prepare the plasma samples. The plasma samples were stored at −80° C.until analysis. An aliquot of dosing formulation was also taken prior tothe dosing and stored at −20° C. for analysis.

TABLE 5 1,3PDS AUC Results in Rats after Oral Administration of ProdrugsDose³ 1,3PDS AUC_(0-Tlast) ID No¹ Vehicle² (mg/kg) (ng · h/mL)⁷1,3PDS(2Na) 1 100 40374 1,3PDS(2Na) 2 100 32104 A4 2 116 14855 A6(Na) 1119 650 A13 1 185 25817 A14 1 161 25972 A16(Na) 2 188 30000 A18(Na) 1189 26146 A20(Na) 1 195 19225 A23(Na) 2 163 19387 A26(Na) 1 154 5456A29(Na) 1 142 3088 A30(Na) 1 167 14040 A32(Na) 1 144 1097 A51 1 17529713 A51 2 175 23270 A52(K) 1 230 18109 A53(Na) 1 159 5778 A58 1 1274734 A60(Na) 2 131 45530 A61 2 133 49388 A62(Na) 2 167 741 A63(Na) 2 1312013 A64 2 155 13501 A65(Na) 2 167 595 A66(Na) 2 179 BLLQ A68(Na) 2 131BLLQ A69 1 144 23423 A69 2 144 9567 A70(Na) 2 185 98.0 A71(Na) 2 1352022 A72(Na) 2 135 2602 A73(Na) 2 135 5582 B11 2 143 5682 B13 3 28811770 B14 3 240 15084 B23 2 245 6033 B29 2   92⁴ 20670 B29 2 184 37717,47664 B29 2  461⁵ 65070 B29 2  921⁶ 98321 B29 3 184 45585 B30 3 23436903 B51(2TFA) 1 359 10756 B58 2   81⁴ 31865 B58 2 162 52982, 53724 B582  809⁶ 188592 B59 2 187 5060 B60 2 195 24258 B61 2 173 33340, 43365 B622 207 10566 B63 2 229 4028 B64 2 195 20687 B65 2 205 14372 B66 2 20710802 B67(2HCl) 2 214 44526, 46223 B68 2 195 14178 B70 2 235 128 B71 2147 BLLQ B72 2 163 BLLQ B73 2 207 1472 B74 2 234 753 B75 2 207 31039,29201 B76 2   86⁴ 22150 B76 2 171 36025, 36606 B76 2  857⁶ 131932 B77 2  86⁴ 19175 B77 2 171 57973, 38230 B77 2  429⁵ 30726 B78 2 171 36767 B802 171 44258 B81 2 147 9572 B82 2 195 13535 B83 2 184 499297 B83 2 184522308 B84 2 158 2953 B85 2 184 222417 B87 2 173 37909 C1 1  74 41103 C12  74 34219 C1 3  74 45637 C2 2   43⁴ 29800 C2 2  86 66542, 58313 C2 2 216⁵ 142985 C3 2 155 10049 D1 2 173 46036, 44860 D1 2  865⁶ 249360 D1 3173 54987 D2 2 189 38053 D3 2   81⁴ 26199 D3 2 162 51842, 61390 D3 2 809⁶ 223842 D4 2 175 47144 D5 2 194 57353 D6 2 184 37036 D7 2 15159543, 57502 D7 2  753⁶ 270641 D8 2 173 51253 G4 1 119 1457 P1(2Na) 2 86 BLLQ ¹A compound can be tested as the parent or a salt form. Whenthe compound is in a salt form, the specific salt form is indicated inthe bracket following the code number: Na, sodium salt; 2Na, disodiumsalt; K potassium salt; 2HCl, dichloride salt; 2TFA,bis(trifluoroacetate) salt. ²Dosing vehicle used: 1, water; 2, 0.5%Methocel ™ in water; 3, 2% benzyl alcohol in corn oil ³Dose of 1,3PDSprodrugs is molar equivalent to 100 mg/kg 1,3PDS(2Na) except whenspecified otherwise ⁴Dose is equimolar to 50 mg/kg 1,3PDS(2Na) ⁵Dose isequimolar to 250 mg/kg of 1,3PDS(2Na) ⁶Dose is equimolar to 500 mg/kg of1,3PDS(2Na) ⁷Two values indicate results from two independentexperiments. BLLQ = below low limit of quantification.

b) PK Study in Monkeys

One group of four non-naïve cynomolgus monkeys (2 males and 2 females)received a single dose of a compound by oral gavage administration withat least a 7-day washout period between each experiment. The dosingformulation was prepared according to Example 40. A representativedosing formulation (5 mL) was taken prior dosing for analysis. Thedosing formulation was administed using a gavage tube attached to aplastic syringe. The dosing volume was 10 mL/kg for all animals; and theactual dosing volume was calculated and adjusted according the mostrecent body weight of each animal. The animals were housed individuallyin stainless steel monkey cages at a conventional animal facility,maintained under 12-h light/dark cycle at 24±3° C. and 50±20% relativehumidity. All animals had access to 5 cookies (Harlan 25% ProteinPrimate Diet #2055) in the morning (at about 07:45) and 5 cookies in theafternoon (at about 16:30) except on the morning of dosing where themorning cookies were given at least 4 hours after the dose. Maximumallowable concentrations of contaminants in the diet (e.g. heavy metals,alfatoxin, organophosphate, chlorinated hydrocarbons and PCB's) werecontrolled and routinely analyzed by the manufacturer. Reverse osmosiswater was available ad libitum at all times. In addition, all animalshad access to a daily enrichment diet (e.g. Prima treats, ice withfruits, popcorn, fruits, vegetables, peanuts, pasta, fruit crunchies orfruity gems). However, no treats were given to any animals within 4hours of dosing. The animals were acclimated to the gavage procedure for3 days during the 7-day pretreatment period. Thereafter, the animalswere acclimated to the oral gavage procedure only if they are more than7 days between administrations of 2 compounds. Prior to the firstdosing, four (4) animals (2 males and 2 females) were assigned to thestudy. Any animal with unacceptable pretreatment data (i.e. clinicalsigns, body weight) would not be included in the study. All animals weresubjected to a detailed physical examination once during the 7-daypretreatment period and weekly thereafter. Cage-side clinical signs(ill, health, behavioral changes, etc.) were recorded once daily duringthe treatment period. Body weights were recorded for all animals onceduring the 7-day pretreatment period and weekly thereafter. All animalswere restrained using a sling apparatus from the completion of the oralgavage until a maximum of 1 hour post-dose to facilitate bloodcollection. All animals were then returned to their respective housingcage for the remaining blood collection period.

Blood samples (approximately 1.0 mL each) were collected via the femoralvein from each animal at the following time-points: Pre-dose, 15, 30min., 1, 2, 4, 6, 8, 12 and 24 h post-dose. Any deviations in bloodsampling times were documented in the report. For each time-point, bloodsamples were collected and split into two tubes containing K₃-EDTA. Oneseries of tubes (for plasma samples) were kept on wet ice pendingcentrifugation (maximum 30 minutes). Samples were centrifuged underrefrigeration (4° C.) at a minimum speed of 3000 rpm for 10 minutes.Plasma were harvested into polypropylene tubes, immediately placed ondry ice and stored frozen (at approximately −80° C.) until shipment. Thesecond series of tubes (whole blood) were immediately placed on dry iceand stored frozen until shipment and analysis.

TABLE 6 PK Parameters for 1,3PDS after Oral Administration of Prodrugsto Monkeys¹ Dose³ C_(max) T_(max) AUC_(0-Tlast) ID No² (mg/kg) (ng/mL)(h) (ng · h/mL) 1,3PDS(2Na) 100 1933 1.0 19573 A23(Na) 172 7818 4.051197 A51 175 10308 2.0 26480 B75 207 9180 1.5 37280 B76 171 21846 2.098971 B77 171 7440 2.0 57079 D5 194 3933 4.0 26369 ¹Pharmacokineticparameter values are mean except for Tmax for which the median ispresented ²See the footnote 1 under Table 5. ³Dose of prodrugs is molarequivalent to 100 mg/kg 1,3PDS.

c) In Vivo Study in Ferrets

One group of three male non-naïve ferrets (domestic strain, >16weeks, >1.2 Kg) were starved for approximately 1.5 h prior toadministration of a dosing formulation. Food was given 2 hours postdose. All animals were dosed with the dosing formulation of a compoundby oral gavage administration at dose level of 0.4 mmole/kg either in0.5% Methocel™ or in water. The dosing volume was adjusted to 5 mL/kg.Clinical signs were recorded throughout the study period. Blood samples(200 μl of blood) were collected, from the jugular vein from each animal(3 animals/group) at time-point of 15 min, 30 min, 1, 2, 4, 6, 8 and 12h post dose, into Sarstedt micro tubes (EDTA K₃E/0.5 ml), kept on iceuntil centrifugation at 4° C. at a minimum speed of 3000 rpm (1620G) for10 min, to prepare plasma samples. Plasma samples were stored frozen at−80° C. pending transfer to analysis. An aliquot of dosing solution (0.5mL) was taken prior to dosing and stored frozen at −20° C. pendingtransfer to analysis. Animals used for multiple studies after a wash outof a minimum twelve day period.

Prodrugs evaluated in ferrets were Compounds A23(Na), A51, A61, B29,B58, B75, B76, B77, B82, B83, C2, D1, D3, D5, and D7. Compounds A23(Na),A51, A61, B29, B76, B77, B82, and B83 were all safe prodrugs and showedno clinical signs at standard dose (0.04 mmol/kg) after oraladministration. After administration of Compound B75, 2 out of 3 animalsshowed abdomen scratching but recovered after 1 h. Administration of B58caused animal vomiting. Compound C2 showed severe toxicity and all thethree animals became sick and had to be killed 4 days after compoundadministration. Administration of Compounds D1, D3, D5, and D7 causeddifferent side effects, ranging from green face (D1) to abdominalcontracting and/or vomiting (D3, D5, and D7).

d) Rat Urine Collection Experiment

Animals (one group of four), dose, and the compound administration werethe same as described in Example 41 (a). Food was given 2 h post dose.Following prodrug administration, animals were housed individually inmetabolic cage; and urine samples were collected from each animal, onepre-dose and one during the period of the first 24 h post-dose. Urinesample was collected in pre-weighed polypropylene tube over dry-ice, andthen stored at −80° C. immediately following collection pending transferto analysis. An aliquot of dosing solution (0.5 mL) was taken prior todosing and stored frozen at −20° C. pending transfer to analysis.

TABLE 7 1,3PDS Urinary Excretion after Oral Administration of ProdrugsID No¹ Dose (mg/kg)² F_(e) (% dose)³ 1,3PDS(2Na) 100 54.2, 49.1 A23(Na)163 44.9 A29(Na) 142  7.8 B29 183 69.0 B58 162 87.5 B61 173 72.1 B68 19532.7 B76 171 22.4, 23.4 B77 171  7.4, 6.7 B83 184 45.5 C2 86 80.4 D1 17371.1 D3 162 79.8 D7 151 85.2 ¹See footnote 1 under Table 5. ²All thecompounds were administrated orally at 0.4 mmole/kg (equivalent to 100mg/kg dose of 1,3PDS(2Na)). All the compounds were dosed in 0.5%Methocel ™. ³F_(e) is calculated from the molar amount of 1,3PDSexcreted in urine divided by the molar amount of prodrug administrated,expressed in percentage. Two values indicate two independentexperiments.

Example 42 Plasma and Urine Sample Analysis a) Plasma Sample Analysis

1,3PDS was extracted from an aliquot of rat, mouse, ferret or monkeyplasma using protein precipitation and then injected into a liquidchromatograph equipped with a tandem mass spectrometry detector.Quantification was done by peak area ratio method. A weighted (1/x²)linear regression was performed to back calculate the concentration ofthe analyte. On the day of analysis, 1 standard curve, a minimum of 2replicates of each QC level and the appropriate study plasma sampleswere analyzed using the following step:

-   -   Vortex the samples.    -   Aliquot 25 μL of each sample into separate 1.5-mL polypropylene        tubes.    -   Add 100 μL of ISWS in appropriate samples.    -   Add 150 μL of chilled acetonitrile and vortex for a few seconds.    -   Centrifuge at 13200 rpm at room temperature for 5 minutes.    -   Transfer the supernatant into a 96-well polypropylene collection        plate and evaporate to dryness (approximately 20 minutes).    -   Reconstitute the residue with 400 μL of dH₂O and vortex the        plate.    -   Centrifuge the plate at 2000 rpm for 2 minutes at room        temperature.    -   Inject samples onto the LC-MS/MS.

b) Urine Sample Analysis

1,3PDS was extracted from an aliquot of urine sample using sampledilution. The diluted sample was then injected into a liquidchromatograph equipped with a tandem mass spectrometry detector.Quantitation was done by peak area ratio method. A weighted (1/x²)Quadratic regression was performed to back calculate the concentrationof the analyte. On the day of analysis, 1 standard curve, a minimum of 2replicates of each QC level and the appropriate study plasma sampleswere analyzed using the following step:

-   -   Vortex the samples.    -   Aliquot 25 μL of each sample into separate 50-mL polypropylene        tubes.    -   Add 100 μL of ISWS in appropriate samples.    -   Add 50 mL of water and vortex adequately.    -   Transfer 400 μL of the solution into a 96-well polypropylene        collection plate.    -   Centrifuge the plate at 2000 rpm for 2 minutes at room        temperature.    -   Inject samples onto the LC-MS/MS.

Example 43 PK Data Analysis

For the various pharmacokinetic studies conducted in rats, ferrets andmonkeys, plasma (and blood) concentration-time data for the prodrug and1,3PDS were analyzed by non-compartmental analysis (NCA) using thesoftware program WinNonlin® Professional Version 5.2.1. In order toconduct the NCA, at least 3 measurable concentrations had to beavailable in a concentration-time profile. The following pharmacokineticparameters were determined for plasma (or blood) data: C_(max), T_(max),AUC_(0-Tlast,,), AUC_(0-∞), λ_(z), and T_(1/2). Since the prodrugs and1,3PDS were administered at equimolar doses, the effect of the prodrugson the bioavailability of 1,3PDS was assessed by comparing the C_(max)and AUC of 1,3PDS after administering a prodrug with that afteradministering 1,3PDS.

Example 44 Bacterial Mutation Tests (Ames Test)

Bacterial mutation tests were performed at Charles River Laboratories toevaluate the mutagenic potential of various prodrugs. Salmonellatyphimurium strains (TA1535, TA1537, TA98, TA100) and Escherichia colistrain WP2 uvrA were treated with prodrugs at concentrations rangingfrom 1.58 to 5000 μg/plate in the presence and absence of a supplementedliver fraction (S9 mix) using the pre-incubation version of thebacterial mutation test. All concentrations of each compound wereevaluated in triplicate. Bacteria were incubated with standard positivecontrol agents, and the response of the various bacterial strains tothese agents confirmed the sensitivity of the test system and theactivity of the S9 mix.

TABLE 8 Results of Bacterial Mutation Tests Result ID No¹ Vehicle Inpresence of S9 In absence of S9 A23(Na) DMSO Negative Negative A29(Na)Water Positive Negative A51 Water Negative Negative A61 Water PositivePositive B29 DMSO Positive Negative B58 DMSO Positive Positive B68 DMSONegative Negative B75 DMSO Negative Negative B76 DMSO Negative NegativeB77 DMSO Negative Negative B78 DMSO Negative Negative B83 DMSO NegativeNegative ¹See footnote 1 below Table 5.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. Any publication, document, patent, patentapplication or publication referred to herein should be construed asincorporated by reference each in their entirety for all purposes.

What is claimed is:
 1. A compound of Formula I:

wherein, R¹ is selected from OR³, —NHC(O)R⁵, —NHC(NH)NHR⁵,—NH(C₅-C₁₀heteroaryl) or a nitrogen atom part of a mono or bicyclicheteroaryl having from 5 to 10 ring members; R² is selected from OR⁴,—NHC(O)R⁵, —NHC(NH)NHR⁵, —NH(C₅-C₁₀heteroaryl) or a nitrogen atom partof a mono or bicyclic heteroaryl having from 5 to 10 ring members, or R¹is a covalent bond and R² is selected from O, NH, NC(O)R⁵, NC(NH)NHR⁵,and N(C₅-C₁₀heteroaryl) when R¹ and R² are taken together with theiradjacent atoms to form a heterocycle; R³ is selected from hydrogen and asubstituted or unsubstituted group selected from C₁-C₁₂alkyl,C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl,C₆-C₁₅aryl, and C₅-C₁₅heteroaryl; R⁴ is a substituted or unsubstitutedgroup selected from C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl,C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl, C₆-C₁₅aryl, andC₅-C₁₅heteroaryl; and R⁵ is selected from hydrogen and a substituted orunsubstituted group selected from C₁-C₁₂alkyl, C₂-C₁₂alkenyl,C₂-C₁₂alkynyl, C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl, C₆-C₁₅aryl, andC₅-C₁₅heteroaryl; or a pharmaceutically acceptable salt or solvatethereof.
 2. The compound of claim 1, wherein said compound is a compoundof Formula II:

wherein, R³ is selected from hydrogen and a substituted or unsubstitutedgroup selected from C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl,C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl, C₆-C₁₅aryl, andC₅-C₁₅heteroaryl; and R⁴ is a substituted or unsubstituted groupselected from C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl,C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl, C₆-C₁₅aryl, andC₅-C₁₅heteroaryl; wherein at least one of R³ and R⁴ is a substitutedbranched C₃-C₈alkyl, a substituted or unsubstituted C₆-C₁₅aryl orC₅-C₁₅heteroaryl group, or a group of Formula B:

wherein, R⁷ and R⁸ are each independently a substituted or unsubstitutedcroup selected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, C₆-C₁₀aryl, C₅-C₁₀heteroaryl,C(O)OH, C(O)OC₁-C₆alkyl, NH₂, NHC(O)OC₁-C₆alkyl; and R²² is a hydrogenatom or a group selected from C₁-C₆alkyl, C(O)OH, or C(O)OC₁-C₆alkyl;and R⁶ is a croup of formula C:

wherein R⁹ is absent; X is selected from the group consisting of OH,NO₂, CN, SH, C(O)OH, C(O)OR¹², OC(O)OR¹², SC(O)OR¹², P(O)(OH)₂,P(O)(OR¹²)₂, P(O)(OR¹²)(OH), OC(O)R¹³, OC(O)NHR¹³, SC(O)R¹³, C(O)R¹⁴,and NHR¹⁵; n is 0; R¹² is a substituted or unsubstituted group selectedfrom C₁-C₆alkyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, C₆aryl,C₅-C₆heteroaryl, benzyl, CH₂R¹⁶, and CH(C₁-C₆alkyl)R¹⁶; R¹³ is asubstituted or unsubstituted group selected from C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, C₆aryl, C₅-C₆heteroaryl, andbenzyl; R¹⁴ is the residue of a natural or unnatural N-coupled aminoacid having an protected or unprotected carboxyl end; R¹⁵ is the residueof a natural or unnatural C-coupled amino acid having an protected orunprotected amino end; and R¹⁶ is selected from the group consisting ofOC(O)C₁-C₆alkyl and OC(O)OC₁-C₆alkyl; or a pharmaceutically acceptablesalt or solvate thereof.
 3. The compound of claim 2, wherein R³ is asubstituted or unsubstituted group selected from C₁-C₁₂alkyl,C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₃-C₁₅cycloalkyl, C₃-C₁₅heterocycloalkyl,C₆-C₁₅aryl, and C₅-C₁₅heteroaryl.
 4. The compound of claim 2, whereinsaid compound is a compound of Formula II-A

wherein, R⁴ is a substituted branched C₃-C₈alkyl, or a substituted orunsubstituted C₆-C₁₅aryl or C₅-C₁₅heteroaryl; or a pharmaceuticallyacceptable salt or solvate thereof. 5-10. (canceled)
 11. The compound ofclaim 2, wherein at least one of R³ and R⁴ is a group of Formula D:

wherein, R¹⁷ in each occurrence is each independently a hydrogen atom ora substituted or unsubstituted group selected from C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl,C₆-C₁₀aryl, C₅-C₁₀heteroaryl, an electron-withdrawing group or asubstituent selected from the group consisting of amino, amido,hydroxyl, alkoxy, acyloxy, alkoxycabonyloxy, and the like; and m is aninteger from 1 to
 5. 12-13. (canceled)
 14. The compound of claim 2,wherein said compound is selected from:

or a pharmaceutically acceptable salt or solvate thereof.
 15. (canceled)16. The compound of 1, wherein said compound is selected from:

or a pharmaceutically acceptable salt or solvate thereof. 17-23.(canceled)
 24. The compound of claim 1, wherein said compound is acompound of Formula IV:

wherein, R¹⁸ is selected from OR³, NH₂, —NHC(O)R⁵, —NHC(NH)NHR⁵,—NH(C₅-C₁₀heteroaryl), —NR²⁰R²¹, R¹⁴, and —NHR¹⁵; R¹⁹ is selected fromNH₂, —NHC(O)R⁵, —NHC(NH)NHR⁵, —NH(C₅-C₁₀heteroaryl), —NR²⁰R²¹, R¹⁴, and—NHR¹⁵; R³, R⁵, R¹⁴, and R¹⁵ are as defined in any one of the precedingclaims; and R²⁰ and R²¹ are taken together with their adjacent nitrogenatom to form a mono or bicyclic heteroaryl having from 5 to 10 ringmembers; or a pharmaceutically acceptable salt or solvate thereof. 25.The compound of claim 24, wherein: R¹⁸ is selected from OR³, —NHC(O)R⁵,—NHC(NH)NHR⁵, —NH(C₅-C₁₀heteroaryl) and —NR²⁰R²¹; R¹⁹ is selected from—NHC(O)R⁵, —NHC(NH)NHR⁵, —NH(C₅-C₁₀heteroaryl) and —NR²⁰R²¹; R³ and R⁵are as defined in any one of the preceding claims; and R²⁰ and R²¹ aretaken together with their adjacent nitrogen atom to form a mono orbicyclic heteroaryl having from 5 to 10 ring members; or apharmaceutically acceptable salt or solvate thereof.
 26. The compound ofclaim 24, wherein said compound is selected from:

or a pharmaceutically acceptable salt or solvate thereof. 27-28.(canceled)
 29. A pharmaceutical composition comprising a compoundaccording to claim 1 together with a pharmaceutically acceptablecarrier. 30-42. (canceled)
 43. A method for treating AA amyloidosis ordiabetic naphropathy, comprising the step of administering to a subjectin need thereof, a therapeutically effective amount of a compound ofclaim 1 such that said AA amyloidosis or diabetic naphropathy istreated.
 44. A method for treating a renal disorder, comprising the stepof administering to a subject in need thereof, a therapeuticallyeffective amount of a compound of claim 1, such that said renal disorderis treated.
 45. The method of claim 43, wherein diabetic nephropathy istreated.
 46. A method for the treatment of metabolic syndrome,hyperglycemia, or diabetes mellitus, comprising the step ofadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of claim 1, such that said metabolic syndrome,hyperglycemia, or diabetes mellitus is treated. 47-48. (canceled) 49.The method of claim 46, wherein said diabetes mellitus is type 1diabetes.
 50. The method of claim 46, wherein said diabetes mellitus istype 2 diabetes.
 51. The method of claim 50, wherein said diabetesmellitus is type 2 diabetes with features of metabolic syndrome.
 52. Amethod for increasing insulin levels circulating in blood in response tofood, decreasing resistance to insulin and/or increasing insulinsensitivity in selected tissues, increasing insulin secretion bypancreatic cells, increasing beta-cells and/or islets of Langerhansneogenesis and/or regeneration of islets of Langerhans or preventingtheir destruction by apoptosis, preventing apoptosis in beta-cells, andstabilizing, restoring, and/or improving beta-cells size, growth and/orfunction, or delaying the requirement for treating a diabetic patientwith exogenous insulin, comprising administering a therapeuticallyeffective amount of a compound of claim 1 to a subject in need thereof.53. (canceled)
 54. The method of claim 43, wherein AA amyloidosis istreated. 55-62. (canceled)